EA014693B1 - Therapeutically active compounds - Google Patents

Abstract

Compounds of formula (1)or a pharmaceutically acceptable derivative thereof, wherein Rand Rindependently represent H, Calkyl, Ccycloalkyl, or halogen; Rrepresents Calkyl, CFor aryl; a represents 1 or 2; R, R, Rand Rindependently represent H, Calkyl, Calkyloxy, CN or halogen, or Rand R, or Rand R, together with the ring to which they are attached form an aryl or heterocyclic fused ring system; X represents C or N; Y represents CHor O; Rrepresents H, CN or halo, but when X represents N then Rrepresents H; may be useful for treating endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), or chronic pelvic pain syndrome.

Description

This invention relates to new compounds and their derivatives, which are suitable for use in therapy, and to methods for their preparation. It also relates to intermediates used in the preparation of such compounds and derivatives, to compositions containing them and to their use.

Endometriosis is a common gynecological disease that occurs in 10-20% of women of reproductive age and manifests itself in the presence of functional ectopic endometrial glands and stroma outside the uterine cavity (Rteijs A. (2001) W., 323, 93-95). Patients with endometriosis can exhibit many different symptoms of varying severity. Typically, these symptoms are dysmenorrhea, but chronic pelvic pain, dyspareunia, difficult bowel movements, menorrhagia, lower abdominal or lower back pain, infertility, swelling, and pain during urination are also symptoms of endometriosis.

Originally described by Uoi Vokyaykku in 1860 (Uoy Kokyaykku S. (1860) ΖίκΟι K.K. bekeIksN yeg Aegh) e ζυ \ U1ep. 37, 577-581) the exact pathogenesis of endometriosis is unclear (^ ίΐζ S.A. (1999) CHshca1 0bk1e1spsk & buyesodu, 42, 566-585; ^ ίΐζ S.A. (2002) Opaezoschos & 0bk1e1ps 1puyoshchina, 53, 52, 52-62 ), but the most common theory is the theory of implantation, or Sampson's theory (Zatrkoy 1.A. (1927) Atepsap 1oigia1 OG 0k1e1psk & buyesodu, 14, 422-429). Sampson's theory suggests that the development of endometriosis is a consequence of retrograde dissemination and implantation of endometrial tissue into the abdominal cavity during menstrual bleeding. After attachment, endometrial fragments receive blood supply and undergo proliferation and secretion cycles under local and systemic hormonal control. In women with open fallopian tubes, retrograde menstrual bleeding appears to be a universal occurrence (Lh.H. (Nysr. A.). This disease often manifests itself as rectovaginal endometriosis or adenomyosis, limited ovarian cystic proliferation of endometrioid tissue, and, most often, peritoneal endometriosis. The main sites of attachment and growth of the lesion within the pelvis are the ovaries, wide and round ligaments, fallopian tubes, neck, vagina, peritoneum and Douglas diverticulum. In the most severe case, endometriosis can cause a deep structural modification of the abdominal cavity, including multiple organ adhesions and fibrosis.

Symptomatic endometriosis can be treated medically and promptly if the intention is to remove the tissue of the ectopic lesion. Surgical intervention can be conservative when they seek to maintain the patient's reproductive potential, or relatively radical in the case of a serious illness, including dissection of the urinary tract, intestines and rectovaginal septum, or complete abdominal hysterectomy and bilateral salpingo-ooferectomy.

Medical pharmacological treatments, such as androgen therapy, danazol and gestrinone, a combination of biKN agonists, buserelin, goserelin, leuprolide, nafarelin and triptorelin, biKN antagonists, cetrorelix and abarelix, as well as progestogens, including medroxyprogesterone, induce atrogesterone, causing medroxyprogesterone. These approaches are not without unwanted side effects; danazol and gestrinone include weight gain, hirsutism, acne, mood changes, and metabolic effects on the cardiovascular system. A group of biRN agonists and antagonists, as it turned out, causes a deep suppression of estrogen, which leads to vasomotor effects (paroxysmal sensations of heat) and a decrease in bone mineral density, which limits their use to only six months of therapy. A group of progestogens, including medroxyprogesterone acetate, suppresses gonadotropins, but does not inhibit ovarian production of estrogen to the same extent as biRN analogues. Side effects include irregular bleeding, bloating, weight gain, and metabolic effects on the cardiovascular system.

Leiomyomas (E1ake O.R., e) a1. (2003) EihuhtoiteSha) NeaNR Retkresyuek, 111, 1037-1054; \ Wa1keg S.L. (2002) Reggie Rgodettek Nail Kekeatsr, 57, 277-294) or uterine fibroids are the most common benign tumors in women and occur in most women by the time of menopause. Although uterine fibroids are the most common indication for hysterectomy in the United States, along with endometriosis, surprisingly little is known about the underlying pathophysiology of this disease. As with endometriosis, the presence of enlarged uterine fibroids is associated with abnormal uterine bleeding, dysmenorrhea, pelvic pain, and infertility. In addition to surgical treatment, it has been shown that therapies commonly used to treat endometriosis, such as biRN analogues or danazole, inhibit the growth of fibroids, causing a reversible hypoestrogenic state (S'Npkr R., Aiy Boa K.B. (1990) Ότυ§8, 39, 523-551; SRpzr R., Aiy Boa, K. L. (1991) Aegiuk 41, 254-288; Ee Leo V., e! A1. (2002) Aegis ZaGe1u, 25, 759-779; NYata N ., e! a1. (2003) EEISu & Z1ep1yu, 79, 735-742). However, in the future, treatment of both uterine fibroids and endometriosis should be based on the development of more effective, well-tolerated and safer drugs than those currently available.

Steroidal progestins (i.e., progesterone receptor agonists) are commonly used in women's healthcare, for example, in contraception and hormone therapy, and for the treatment of gynecological disorders. Recent studies on women and primates also show that antagonists

- 1 014693 progesterone receptors may find use in contraception and for the treatment of reproductive disorders such as fibromas and endometriosis. Currently, all clinically available progesterone receptor agonists and antagonists are steroid compounds. They often cause various side effects due to their functional interactions with other steroid receptors or due to the effects associated with their steroid metabolites (Lushpsksg. Kstsyaty e! ! e. CoInddsGS.Ra. I8A. 8et1Itat ίη Kergoyis! Keix (2005). 23 (1). 46-57).

Progesterone receptor antagonists [antiprogestins (ARCs)]. including the most significant members of this class mifepristone (KI-486; Koikke1 ISLAE. Cotastche. France). onapriston (ΖΚ 98,299; 8syepid AO). ΖΚ 137 316 and ΖΚ-230 211. are compounds. which bind to progesterone receptors (PKs) and prevent progesterone-induced gene expression (δρίΐζ 1.M. (2003) 8! etojk. 68. 981-993). Acting on an estrogen-activated endometrium. progesterone plays a significant role in the differentiation and ductal morphogenesis of endometrial tissue. and also participates in the inhibition of myometrial contractility and in the polarization responses of the leukocyte TH1 / TH2. which are critical for embryo implantation and pregnancy support. Numerous studies have been conducted on the potential beneficial effects of antiprogestins on the signs and symptoms of endometriosis (Cgo \ u Ό.Κ .. e! A1. (1996) 1it1 o! Sysssa1 Eiospio1odu & Me! Aioykt. 81. 19331939; Ke !! .. e! a1. (1996) Eg1iu & 8! eg11yu. 65. 23-28; Ke !! e1 b.M .. e! a1. (1998) Ategsai 1oita1 o! Ok! e1psk & Suiaesodu. 178. 1151 -1156) and uterine fibroids (E1kshdet 8.N .. e! A1. (2003) Ok! E1psk & Suiaesodu. 101. 243-250; MigrNu A.A. aiy Sak! E11aio. Ρ.Ζ. (1994) Sipsi! Orshuy ίη Ok! E1psk & Suiaesokdu. 6. 269-278; MigrNu A.A. .. e! A1. (1995) Etyuyu & 8! Ep1yu. 63. 761-766; 8! Esaeyeg 1 .. Rpyk. ! a1. (2004) Bk! e! psk & Suiaesoodu. 103. 1331-1336; Waid Υ .. e! A1. (1996) Siyyeke. Unlike analogues of CKN and other conventional pharmacological approaches, antiprogestins. especially mifepristone. apparently. able to reduce the volume of lesions or fibromas. maintaining a tonic level of ovarian secretion of estrogen. Such antiprogestins cause amenorrhea and endometrial densification. and. apparently. sufficiently protect against rapid estrogen-dependent loss of bone mass (Sgote B.K .. e! a1. (1996) 1oitia1 o! Syssha1 Eiospio1odu & Me! ao11kt. 81. 1933-1939). In contrast to them. CuKN analogues cause a rapid decrease in bone mineral density. which is a clinical feature. which limits the duration of treatment with their use to six months. Although mifepristone is a powerful antiprogestin. it also has similar antiglucocorticoid activity. Outside of the palliative treatment of hypercortisolism with Cushing's syndrome (CHI 1. \ ν .. e! A1. (2001) 1. C11i Eiyospio1 Me! Ab .. 86. 3568-3573; 8ayot O .. aiy Si! 1eg. S.V. 1t. (1996) С1ш Ок! Е! Suiaeso1. 39. 506-510; 8ρί! Ζ. 1.M. (2003) 8! Etojyk. 68. 981-993; Wai Look R.E .. aiy νο and Netkey N. (1995) Nitai Kertoyisoyoi Irya! E 1. 19-34}. Antiglucocorticoid activity is an undesirable feature of mifepristone and potentially many representatives of the steroid classes of antiprogestins.

The following class of steroidal and non-steroidal compounds has also been described. which are called progesterone receptor modulators (RCMs or mesoprogestins). including asoprinsil (1867. benzaldehyde. 4 - [(11c.17c) -17-methoxy-17- (methoxymethyl) -3-oxoestra-4.9-dien-11-yl] -. 1 oxime; 1 ether. TAP). 1912.1956. L042. In addition to their potential suitability in hormone replacement therapy and as contraceptives can be assumed. that these classes of compounds can be used in the treatment of endometriosis and uterine leiomyomas (0Π ^ η1ίκζ. K .. e! a1. (2004) 8ets Kergo May .. 22. 113-119; ΟΉ ^ η1ίκζ. K .. e! a1. (2002) Aiia1k o! 1ye no. \ Ν Υο ^ to Asayet o! 8skisek. 955. 373-388; yiksikkui 389-393; PeMaio Ό .. e! A1. (2003) 8! Ee1yk. 68. 1019-1032) . Asoprinsil and structurally related RCMs differ from antiprogestins and progestins in animal models. showing partial progestogen activity. eg. in the endometrium of the rabbit (McFail test (McRNay M.K. (1934) 1 oitia1 o! ryukyuodu. 83. 145-156)) and the vagina of the Guinea pig. Preclinical studies with asopril on primates have shown. that RCMs suppress endometrial growth and, unlike the effects of progestins, do not inhibit endometrial expression of EC and PK (0? 1ι \ νί · ι1ίκζ K .. e! a1. (2000) 8! etojyk 65. 741-751; BeMaio Ό .. e ! a1. (2003) 8! etojk. 68. 1019-1032; E1deg V .. e! a1. (2000) 8! etojk. 65. 713-723).

Was found. that the compounds of the present invention have useful pharmaceutical properties. They can be used to treat endometriosis. uterine fibroids (leiomyomatous lesions) and menorrhagia. adenomyosis. primary and secondary dysmenorrhea (including symptoms of dyspareunia. difficult bowel movements and chronic pelvic pain). chronic pelvic pain syndrome. early puberty. cervical maturation. contraception (urgent cases). breast cancer. ovarian cancer. endometrial cancer. prostate cancer. lung cancer. testicular cancer. stomach cancer. meningiomas. disturbing conditions. premenstrual syndrome. premenstrual dysphoric disorder. alcohol abuse and muscle peroneal atrophy or Charcot-Maritut disease.

Of particular interest are the following diseases or disorders: endometriosis. uterine fibroids (leiomyomatous lesions). menorrhagia. adenomyosis. primary and secondary dysmenorrhea (including symptoms of dyspareunia. obstructed bowel movements and chronic pelvic pain) and chrome syndrome

- 20144693 pelvic pain.

In particular, the compounds and derivatives of the present invention exhibit activity as progesterone receptor antagonists and can be used for treatment in cases where progesterone receptor antagonism is indicated.

More specifically, the compounds and derivatives of the present invention can be used to treat endometriosis and / or uterine fibroids (leiomyomatous formations).

The international patent application SHO 02/085860 describes pyrazole derivatives of the formula

in which K ¹ , K ² , K ³ and K ⁴ have values defined there that are modulators of HIV reverse transcriptase.

According to the present invention, an object of the invention is a compound of formula (I)

or a pharmaceutically acceptable derivative thereof, in which K ¹ and K ^{3 are} independently H, C1-6 alkyl, C3-8 cycloalkyl or halogen; K ² is C 1-6 alkyl, CP ₃ or aryl;

a is 1 or 2;

5 7 8 4 5

K, K, K and K independently represent H, C _1-6 alkyl, C _1-6 alkyloxy, ΠΝ or halogen, or K and K, or K ⁷ and K ⁸ , together with the ring to which they are attached form aryl or a heterocyclic fused ring system;

X is C or Ν;

Υ is CH ₂ or O and

K ⁶ is H, ΠΝ or halogen, but when X is Ν, then K ^{6 is} absent.

In the above definitions, alkyl groups containing the required number of carbon atoms, unless otherwise indicated, may have a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkyloxy include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term halogen means fluoro, chloro, bromo or iodo.

The aryl rings included in the definition of aryl are phenyl or naphthyl.

The heterocycles included in the definitions of the heterocyclic nucleus are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isinolinazolinyl, and quinoxalinyl, together with partially or fully saturated versions thereof, as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxazepanil and morpholinyl.

In an embodiment of the invention, K ¹ is C _1-6 alkyl or C _3-8 cycloalkyl.

In another embodiment, K ² is C _1-6 alkyl.

In another embodiment, K ³ is C _1-6 alkyl or C _3-8 cycloalkyl.

In another embodiment, K ⁴ is N.

In another embodiment, K ⁵ is H, C _1-6 alkyl or halogen.

In another embodiment, K ⁴ and K ⁵ together represent a phenyl or pyridinyl ring fused to the ring to which they are attached. Preferably, K ⁴ and K ⁵ together denote a phenyl ring fused to the ring to which they are attached.

In another embodiment, K ⁶ is CX

In another embodiment, K ⁷ is H, C _1-6 alkyl or halogen.

In another embodiment, K ⁸ is H.

In another embodiment, K ⁷ and K ⁸ together represent a phenyl or pyridinyl ring fused to the ring to which they are attached. Preferably, K ⁷ and K ⁸ together denote a phenyl ring fused to the ring to which they are attached.

In another embodiment, Υ is O.

In another embodiment, halogen is fluoro or chloro. Preferred compounds of the present invention are 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile;

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4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile; 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

2- chloro-4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2-fluorobenzonitrile;

3- chloro-4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile ;.

4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -3-fluorobenzonitrile; 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -3-methoxybenzonitrile;

4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) naphthalene-1-carbonitrile;

5- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) quinoline-8-carbonitrile; 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) quinoline;

4- (4-chloro-3-fluorophenoxy) -3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazole;

3.5-dicyclopropyl-4- (3,4-difluorophenoxy) -1-methanesulfonylmethyl-1H-pyrazole;

3.5-dicyclopropyl-1-methanesulfonylmethyl-4- (3,4,5-trifluorophenoxy) -1H-pyrazole;

3.5-dicyclopropyl-4- (3,5-difluorophenoxy) -1-methanesulfonylmethyl-1H-pyrazole;

3.5-dicyclopropyl-1-methanesulfonylmethyl-4- (2,4,5-trifluorophenoxy) -1H-pyrazole;

4- (3-cyclopropyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile;

4- (5-cyclopropyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile; 4- (3-cyclopropyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

4- (5-cyclopropyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

4- (1-methanesulfonylmethyl-3,5-dimethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

4- (3,5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile;

4- (3,5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile; 4- (3,5-di-tert-butyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile;

4- (3-tert-butyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) benzonitrile;

4- (5-tert-butyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) benzonitrile;

4- (3-chloro-5-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile; 4- (5-chloro-3-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

4- (3-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile; 4- (5-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile;

4- (3,5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-ylmethyl) benzonitrile;

4- (3,5-dicyclopropyl-1-trifluoromethanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3,5-dicyclopropyl-1-ethanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile; 4- [3,5-dicyclopropyl-1- (propan-2-sulfonylmethyl) -1H-pyrazol-4-yloxy] benzonitrile; 4- [3,5-dicyclopropyl-1- (2-methylpropan-2-sulfonylmethyl) -1H-pyrazol-4-yloxy] benzonitrile;

4- (1-benzenesulfonylmethyl-3,5-dicyclopropyl-1H-pyrazol-4-yloxy) benzonitrile;

4- (3,5-diethyl-1-methanesulfinylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile; 4- (3,5-diethyl-1-methanesulfinylmethyl-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile; and their pharmaceutically acceptable derivatives.

The above-described embodiments of the invention may be combined with one or more other embodiments, such that in other embodiments, two or more variables are defined more specifically in combination. For example, another embodiment is within the scope of the invention in which the variables K ¹ , B ^2, and b all have more limited definitions that they have in the more specific embodiments described above. All such combinations of the more specific embodiments described and defined above are within the scope of the invention.

Pharmaceutically acceptable derivatives of the compounds of formula (I) according to the invention include their salts, solvates, complexes, polymorphs and crystalline forms, prodrugs, stereoisomers, geometric isomers, tautomeric forms and isotopic variations of the compounds of formula (I). Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) include salts, solvates, esters and amides of the compounds of formula (I). More preferably, pharmaceutically acceptable derivatives of the compounds of formula (I) are salts and solvates.

Pharmaceutically acceptable salts of the compounds of formula (I) include their acid and base addition salts.

Suitable acid addition salts are derived from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, giblozenate, gibenosate, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyrhydrofluphosphate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and k inofoat.

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Suitable base salts are prepared from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

You can also get hemispheres with acids and bases, for example hemisulfate and hemispheres of calcium.

For suitable salts, see NabbOoc οί Pbagtaseibs1 8a11k: Prgoregiek, 8c1ce1up. aib Ike bj 81a111 aib ^ ehti1b (^ eu-USN, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared in one or more of three ways:

(ί) reacting a compound of formula (I) with a desired acid or base;

(ΐΐ) removing an acid labile or base protecting group from a suitable precursor of a compound of formula (I) or opening the ring of a suitable cyclic precursor, for example lactone or lactam, using the desired acid or base, or (ίίί) converting one salt of a compound of formula (I) to another reaction with a suitable acid or base, or through a suitable ion exchange column.

All three reactions are usually performed in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the final salt can vary from complete ionization to an almost complete absence of ionization.

The compounds of the invention can exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term amorphous refers to a state in which the material is disordered at the molecular level and, depending on temperature, may show the physical properties of a solid or liquid substance. Typically, such materials do not provide distinctive X-ray diffraction patterns and, showing the properties of a solid, are more formally described as liquid. After heating, a change in properties occurs from those of a solid to the properties of a liquid substance, which is characterized by a change in state, usually of the second order (glass transition). The term crystalline refers to a solid phase in which the material has a constant ordered internal structure at the molecular level and gives a distinctive refractive structure in x-rays with certain peaks. Such materials, when sufficiently heated, also show the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, usually of the first order (melting point).

The compounds of the invention may also exist in solvated and unsolvated forms. The term “solvate” means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example ethanol. The term hydrate is used when the specified solvent is water.

The currently used classification system for organic hydrates is a system that determines the hydrates of an isolated area, channel, or hydrates coordinated by a metal ion - see P1utogr1p8sh ίη P11agtasei1a 8o11bk Lu K.K Motk (Eb. N.O. Vgy1ash, Magse1 Eekkeg, 1995 ) Isolated site hydrates are those in which water molecules are isolated from direct contact with each other by organic molecules. In channel hydrates, water molecules lie in the channels of the lattice, where they are adjacent to other water molecules. In hydrates coordinated by a metal ion, water molecules are linked to a metal ion.

When the solvent or water is firmly bound, the complex will have a clear stoichiometry regardless of humidity. When, however, the solvent or water is loosely coupled, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry is the norm.

Also included in the scope of the invention are multicomponent complexes (except salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (inclusion drug-host complexes) and co-crystals. The latter are usually defined as crystalline complexes of neutral molecular components, which are linked through non-covalent interactions, but can also be complexes of a neutral molecule with a salt. Co-crystals can be obtained by crystallization of the melt, recrystallization from solvents, or by physically grinding the components together - see Cet. Sottip, 17, 1889-1896, O. L1tag88op apb M.1. 2a ^ oo1ko (2004). For a general overview of multicomponent complexes, see 1. Pbmag. 8c1, 64 (8), 1269-1288, Ls Na1eL11ap (Lidik !, 1975).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) if they are placed under suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the state of an ideal liquid (melt or solution). Mesomorphism resulting from a change in temperature is described as thermotropic, and resulting from the addition of a second component, such as water or another solvent, is described as lyotropic. Compounds that have the potential to form lyotropic mesophases are described as amphiphilic and consist of molecules that have ionic (such as

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-COO'Ya ⁺ , -COO ^- K ⁺ or -8O3'Ya ⁺ ) or non-ionic (such as -Ν'Ν ⁺ (CH3) ₃ ) polar main group. For more information, see Sigkiyk 1bf Po1atshd M1goksore Liu Ν.Η. Naiotiei A. A. 8! 4 ' ¹ ' EiShoi (Ei ^ aty Lgpo1y. 1970).

Further all references to compounds of formula (I) include references to their salts. solvates. multicomponent complexes and liquid crystals and solvates. multicomponent complexes and liquid crystals of their salts.

As indicated above. the so-called prodrugs of the compounds of formula (I) are also within the scope of the invention. So. certain derivatives of the compounds of formula (I). which in themselves may or may not have low pharmacological activity. can be converted to compounds of formula (I). having the desired activity. eg. as a result of hydrolytic cleavage when introduced into or applied to the body. Such derivatives are referred to as prodrugs. Further information regarding the use of prodrugs can be found in the Proc. wo1. 14. AC8 8outrokst 8pek (T. Shdisy ay V. 8! E11a) and VyuuetuSe Sategk ίη Aegis Ietzdi. Regdata Rgekk. 1987 (Her. E.V. Yaosye. Atepsai Rhartaseijs1 Akkoaayoi).

Prodrugs in accordance with the invention can be obtained by replacing suitable functional groups. present in the compounds of formula (I). certain groups. known to specialists as pro-groups. as described. eg. in Ei ^ di o £ Rtoitidk b. N. Viidai (E1keu1et. 1985).

Some examples of prodrugs in accordance with the invention include:

(ί) if the compound of formula (I) contains an alcohol functional group (—OH). its ether. for example a connection. wherein the hydrogen atom of the alcohol functionality of the compound of formula (I) is replaced by _(C1-C6) alkanoyloxymethyl; and (i) if the compound of formula (I) contains a primary or secondary functional amino group (-ΝΗ ₂ or -ΝΗΕ. where I Ψ H). its amide. for example a connection. in which, depending on the circumstances, one or both hydrogen atoms of the functional amino group of the compound of the formula (I) are replaced by (-C1 ₀ ) alkanoyl.

Other examples of substitution groups in accordance with the preceding examples and examples of other types of prodrugs can be found in the above references.

Besides. some compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included in the scope of the invention are metabolites of the compounds of formula (I). that is, connections. which are formed by the administration of the drug. Thus. metabolites of the compounds of formula (I) are included within the scope of the invention. when they are formed.

The compounds of formula (I). containing one or more asymmetric carbon atoms. may exist as two or more stereoisomers. If the compound of formula (I) contains an alkenyl or alkenylene group. geometric cis / trans (or Ζ / E) isomers are possible. If the structural isomers mutually transform into each other through a low energy barrier. tautomeric isomerism (tautomerism) may occur. It can take the form of proton tautomerism in the compounds of formula (I). containing. eg. imino. keto or oxime group. or the so-called valence tautomerism in compounds. which contain an aromatic group. Therefore. that a single compound may exhibit more than one type of isomerism.

All stereoisomers are included within the scope of the present invention. geometric isomers and tautomeric forms of the compounds of formula (I). including connections. showing more than one type of isomerism. and mixtures of one or more of them. Also within the scope of the invention are salts of addition with an acid or base. in which the counterion is optically active. e.g. y-lactate or 1-lysine. or racemic forms. eg. y1-tartrate or y1-arginine.

Cis / trans isomers can be separated by conventional techniques. known to the specialist. for example, chromatography and fractional crystallization.

Conventional methods for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or salt or derivative racemate) using. eg. chiral high performance liquid chromatography (HPLC).

Alternatively. the racemate (or racemic precursor) can be reacted with a suitable optically active compound. for example alcohol. or in case. if the compound of formula (I) contains an acidic or basic group. with base or acid. such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization. and one or both diastereoisomers can be converted to the corresponding pure enantiomer (s) by means. known to the specialist.

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography. usually HPLC. on an asymmetric resin with a mobile phase. consisting of hydrocarbon. usually heptane or hexane. containing from 0 to 50 vol.% isopropanol. usually from 2 to 20 and from 0 to 5 vol.% alkylamine. usually 0.1% diethylamine. Con

- 6 014693 centration of the eluate provides an enriched mixture.

When the racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) indicated above when one homogeneous crystal form is formed containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate when two forms of crystal are formed in equimolar amounts, each of which contains a single enantiomer.

Although both crystalline forms in the racemic mixture have identical physical properties, they can have different physical properties compared to a true racemate. Racemic mixtures can be resolved by conventional techniques known to the skilled person — see, for example, 81gcso11C1B51u0 £ Otdel Sotroipbk E. E. ΕΙίοΙ aib 8.N. \ Ubsp (\ Upsu. 1994).

The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number other than the atomic mass or mass number that prevails in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ C1, fluorine such as ¹⁸ P, iodine, such as I and I, nitrogen, such as N and Ν, oxygen, such as O, O and O, phosphorus, such as ³² P, and sulfur, such as ³⁵ 8.

Some isotope-labeled compounds of formula (I), for example, those that include a radioactive isotope, can be used in studies of the distribution of the drug and / or substrate in the tissue. The radioactive isotope tritium, that is, ³ N, and carbon-14, that is, ¹⁴ C, are especially suitable for this purpose because of the ease of their inclusion and the availability of detection tools.

Substitution with heavier isotopes such as deuterium, i.e. ² N, may present certain therapeutic advantages due to greater metabolic stability, for example, an increased half-life of ίη νίνο or a reduced required dose, and therefore may be preferred in some circumstances.

Substitution with isotopes emitting positrons, such as ¹¹ C, ¹⁸ P, ¹⁵ O, and ¹³ Ν, can be used in studies of Positron Emission Topography (PET) to study substrate receptor occupation.

Isotope-labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparation examples using a suitable isotope-labeled reagent instead of the unlabeled reagent used previously.

Pharmaceutically acceptable solvates in accordance with the invention include those in which the crystallization solvent may be replaced by an isotope, for example, E ₂ O, b ₆ -acetone, b ₆ -DMSO.

The compounds of formula (I) should be evaluated for their biopharmaceutical properties, such as solubility and stability of the solution (in the pH range), permeability, etc., to select the most suitable dosage form and route of administration for the treatment of the proposed indication.

The compounds of the invention for pharmaceutical use may be administered in the form of crystalline or amorphous products. They can be obtained, for example, as solid tampons, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporation drying. For this purpose, microwave or high-frequency drying can be used.

The compounds of the invention may be administered individually or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in the form of any combination of the above).

The compounds of the present invention may be administered in combination with COX inhibitors. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more COX inhibitors in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

COX inhibitors suitable for combination with the compounds of the present invention include, but are not limited to:

(ί) ibuprofen, naproxen, benoxaprofen, flurbiprofen, phenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, myroprofen, thioxaprofen, buprofenopinoplofenopinfufinoprofen, tirolofupinoplofupinoprofen, tiaprofenoplofupinoprolofen, tiaprofenoprolofen , diclofenac, fenclofenac, alklofenac, ibufenac, isoxepac, furofenac, thiopinac, zidomethacin, acetylsalicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenfenamic acid, tofenamic acid, tofenamic acid, tofenamic acid, roizvodnye podophyllotoxin, acemetacin, droxicam, floctafenine, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oksipinak, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic sour

- 7 014693 tu, cholinium magnesium trisalicylate, salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam and 4- (nitrooxy) butyl ether 2-fluoro-a-methyl [1,1'-biphenyl] -4-acetic acid (see \ Success. S1 a1., Egor. I. Ryagtaso. 1, 453: 319-324 (2002));

(ίί) meloxicam (CA8 registration number 71125-38-7, described in US Pat. No. 4,233,399) or a pharmaceutically acceptable salt or prodrug thereof;

(ίίί) celecoxib (US patent 5466823), valdecoxib (US patent 5633272), deracoxib (US patent 5521207), rofecoxib (US patent 5474995), etoricoxib (international patent application publication No. νθ 98/03484), LE-522 (Publication Japanese Patent Application No. 9052882) or a pharmaceutically acceptable salt or prodrug thereof;

(ίν) parecoxib (described in US Pat. No. 5,932,598), which is a therapeutically effective prodrug of a selective tricyclic Cox-2 valdecoxib inhibitor (described in US Pat. No. 5,633,272), in particular sodium parecoxib;

(ν) АВТ-963 (described in the international publication of patent application No. νθ 00/24719), (νί) nimesulide (described in US patent 3840597), flosulide (discussed in 1. Sayeg, Exp. Orth. Thieg. Ra1ep18, 8 (1), 21-29 (1997)), N8-398 (disclosed in US Pat. No. 4,885,367), 8-8381 (described in US Pat. No. 6,034,256), BM8-347070 (described in US Pat. No. 6,180,651), 8-2474 (described in European Patent Publication No. 595546) and MK-966 (described in US Pat. No. 5,968,974);

(νίί) darbufelon (RPheg), C8-502 (8apuo), bA8 34475 (A1sh1ga11 Rgoigyagta), bA8 34555 (A1tya11 Rgoigyagta), 8-33516 (8eMega), 8Ό8381 (Ul. 347070 (Bn51o1 Muegk 8di1b, described in US patent 6180651), MK-966 (Megsk), L-783003 (Megsk), T-614 (Touata), T-1367 (Sygoksheps), L-748731 (Megsk), CT3 ( Abaijs Ryagtaseeysa1), SSR-28238 (SHAI ^), BP-389 (Vyuog / 8yegeg), SK-253035 (C1axo ^ e11sote), 6-dioxo-9H-purin-8-yl-cinnamic acid (C1axo / Ue11sote) and 8-2474 (8Jopof).

The compounds of the present invention may be administered in combination with PDE5 inhibitors. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more PDE5 inhibitors in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

RPEU inhibitors suitable for combination with the compounds of the present invention include, but are not limited to:

(ί) preferably 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-

1.6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7-one (sildenafil, for example, marketed as U1adga®), also known as 1 - [[3- (6,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo [4,3-b] pyrimidin-5yl) -4ethoxyphenyl] sulfonyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -

1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7-one (see EP-A-0526004); 3-ethyl-5- [5- (4 ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-b ] pyrimidin-7-one (see νθ 98/49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H- pyrazolo [4,3-b] pyrimidin-7-one (see νθ 99/54333); (+) - 3-ethyl-5- [5 (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (K) -methylethoxy) pyridin-3-yl] -2-methyl-2,6 -dihydro7H-pyrazolo [4,3-b] pyrimidin-7-one, also known as 3-ethyl-5- {5- [4-ethylpiperazin-1-ylsulfonyl] -2 ([(1K) -2-methoxy- 1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7-one (see νθ 99/54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -

2.6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7-one, also known as 1- {6-ethoxy-5- [3-ethyl-6,7-dihydro-

2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-b] pyrimidin-5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine (see νθ 01/27113, example 8); 5- [2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl2- (1-methylpiperidin-4-yl) -2,6-dihydro-7H-pyrazolo [4 , 3-b] pyrimidin-7-one (see νθ 01/27113, example 15); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-] pyrimidine- 7-one (see νθ 01/27113, example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7- he (see νθ 01/27112, example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-b] pyrimidine- 7-one (see νθ 01/27112, example 132); (6K, 12aK) -2,3,6,7,12,12a-hexahydro-2-methyl-6 (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4- B] indole-1,4-dione (tadalafil, 1C-351, C1a118®), that is, the compound from examples 78 and 95 of published international application νθ 95/19978, as well as the compounds from examples 1, 3, 7 and 8; 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7propyl-3H-imidazo [5.1-1] [1,2,4] triazine- 4-one (vardenafil, LEU1TKA®), also known as 1 - [[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-1] -a8-1riazin-2-yl ) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine, i.e. the compound of Examples 20, 19, 337 and 336 of published international application νθ 99/24433; the compound of example 11 of published international application νθ 93/07124 (E18A1); compounds 3 and 14 of Co1e11a ER, 1. Meb. Siet., 2000, 43, 1257; 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline; Ν [[3- (4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-b] pyrimidin-5-yl) -4-propoxyphenyl] sulfonyl] -1methyl- 2-pyrrolidine propanamide [PA-8159 (Example 68 of νθ 00/27848)]; and 7,8-dihydro-8-oxo-6- [2-8014693 propoxyphenyl] -1H-imidazo [4,5-d] quinazoline and 1- [3- [1 - [(4-fluorophenyl) methyl] - 7,8-dihydro-8-oxo-1 Nimidazo [4,5-d] quinazolin-6-yl] -4-propoxyphenyl] carboxamide; 4 - [(3-chloro-4-methoxybenzyl) amino] -2 [(28) -2- (hydroxymethyl) pyrrolidin-1-yl] -Y- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide (TA1790) ; 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-6] pyrimidin-5-yl) -Y- [2- (1-methylpyrrolidin2-yl) ethyl] -4-propoxybenzene sulfamide (ΌΑ 8159) and their pharmaceutically acceptable salts;

(ίί) 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) propoxy] -3 (2H) pyridazinone; 1- [4 - [(1,3benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinosolinyl] -4-piperidinecarboxylic acid, monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) phenylmethyl-5-methylcyclopent-4,5] imidazo [2,1-b] purin-4 ( 3H) -one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl 1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5 (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-b) pyrimidin-7-one; 1 - [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt; P11agtargo) ec15 No. 4516 (C1axo ^ e11sote); P11agtargo) ec15 No. 5051 (Vaueg); P11agtargo) e15 No. 5064 (Kuota Nakko; see \ UO 96/26940); Rkagtargo) EU15 No. 5069 (8skegtd R1oidk); CE-196960 (C1axo \ Ue11sote); E-8010 and E-4010 (Ека1); Wow-38-3045 and 38-9456 (Woweg); EYA229934 and EY226807 (Eirzata); and 8sy-51866.

Preferably, the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil, ΌΑ-8159 and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl ] -2,6-dihydro7H-pyrazolo [4,3-b] pyrimidin-7-one. Most preferably, the PDE5 inhibitor is sildenafil and its pharmaceutically acceptable salts. A preferred salt is sildenafil citrate.

The compounds of the present invention may be administered in combination with a U1a antagonist. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more U1a antagonists in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

A suitable vasopressin U1a receptor antagonist is, for example, (4- [4-benzyl-5- (4methoxy-piperidin-1-methylmethyl) -4H- [1,2,4] triazol-3-yl] -3,4,5 , 6-tetrahydro-2H- [1,2 '] bipyridinyl), which corresponds to example 26 in \ UO 2004/37809. Another example of a suitable vasopressin U1a receptor antagonist is 8-chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6dihydro-4H- 2,3,5,10 L-tetraazobenzo [e] azulene, or a pharmaceutically acceptable salt or solvate thereof, which corresponds to Example 5 in UO 04/074291.

Other examples of the vasopressin U1a receptor antagonist for use in the invention are 8YA49049 (relkovaptan), atosiban (Ttas! Osbe®), conivaptan (ΥΜ-087), URA-985, CI-385004, vasotocin and OPC21268. Additionally, U1a receptor antagonists described in XVO 01/58880 are suitable for use in the invention.

The compounds of the present invention may be administered in combination with an alpha adrenergic receptor antagonist (also known as an α-adrenergic receptor blocker, an α-receptor blocker or an α-blocker). Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more alpha adrenergic receptor antagonists in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

Antagonists of the α ₁ -adrenergic receptor suitable for use in the present invention include, but are not limited to, terazosin (US patent 4026894), doxazosin (US patent 4188390), prazosin (US patent 3511836), bunazosin (US patent 3920636), alfuzosin (US patent 4315007), naphthopidyl (US patent 3997666), tamsulosin (US patent 4703063), silodosin (US patent 5387603), phentolamine and phentolamine mesylate (US patent 2503059), trazodone (US patent 3381009), indoramine (US patent 3527761) , phenoxybenzamine (US Pat. No. 2,599,000), Rauwolfia alkaloids (a natural product from the Rauvo bush Lphia snake), Vesogbab 15/2739 (^ О 93/17007), 8ΝΑΡ 1069 V 94/08040 e.g. 3, compound 9, p. 77 and tab. 3, p. 86), 85089 (No. O 94/10989), YA817053 (US 5436264), 8L 89.0591 (EP 435749) and abanohil (EP 100200); compounds disclosed in international publication VO 03/076427, in particular 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro [1,6] -naphthyridin-6 (5H) -yl) -4 (3H) quinazolinone (Example 11), and the compounds disclosed in international publication VO 98/30560, in particular 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido1,2,3,4-tetrahydroisoquinol- 2-yl) -5- (2-pyridyl) quinazoline (Example 19); and their pharmaceutically acceptable derivatives. Preferred antagonists of the α-adrenergic receptor are doxazosin, 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro [1,6] -naphthyridin-6 (5H) -yl) -4 (3H ) quinazolinone and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline and their pharmaceutically acceptable derivatives. Of particular interest is 4-amino-6,7dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolinemesylate (see \ ν () 01 / 64672).

A ₂ adrenergic receptor antagonists suitable for the present invention include

- 9 014693 dibenamine (ΌΕ 824208), tolazoline (US patent 2161938), trimazosin (US patent 3669968), efaroxane (EP 71368), yohimbine (CoIbett M.K., e! A1., Rbattaso 1. Keu., 35, 143 -180 (1987)), idazoxane (EP 33655) and clonidine (U.S. Patent 3,202,660).

Non-selective α-adrenergic receptor antagonists suitable for the present invention include dapiprazole (US Pat. No. 4,252,721).

The compounds of the present invention may be administered in combination with a 5-alpha reductase inhibitor. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more 5-alpha reductase inhibitors in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

5-alpha reductase inhibitors include 5-alpha reductase isoenzyme 2 inhibitors. Suitable compounds for use in the present invention are PKO8SAK (also known as finasteride, US Pat. 93/23040, 93/23039, 93/23376, 93/23419, EP 0572165 and AO 93/23051.

The compounds of the present invention may be administered in combination with an agent that lowers estrogen levels or which counteracts an estrogen receptor. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more agents that lower estrogen levels or counteract the estrogen receptor, in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

Agents that lower estrogen levels include gonadotropin releasing hormone agonists (SPK), SPK antagonists, and estrogen synthesis inhibitors. Agents that counteract the estrogen receptor, i.e., estrogen receptor antagonists, include antiestrogens.

SpKN agonists suitable for the present invention include leuprorelin (Rgok! Ar Aue1b), buserelin (8irte £ ac! - 8yte), goserelin (2o1abeh - Ak! Ha 2peza), tryptorelin (Eesarer1u1 1kepep), nafarelin, 8eate deslorelin (8otadatb - 8Byte) and histrelin / supprelin (OPyo Ryattasei! 1ca1 Sotr / 8Byte).

SpKN antagonists suitable for the present invention include teverelix (also known as antarelix), abarelix (P1epakhs - Rtaesch Rbagtaseibs1k 1ps), cetrorelix (SeKobbe - A8TA Mebua) and ganirelix (Ogda1i! Gap - Ogdapop).

Antiestrogens suitable for the present invention include tamoxifen, Eac1obec (Ak! Ha 2epesa), idoxifen (see Corresponding e! A1. (1995) Sapseg Kek., 55, 1070-1074), raloxifene or EM-652 (L. e. , e! a1., (2001) 1. kuto1b Vusyet. Mo1. Vu1., 79, 213).

Estrogen synthesis inhibitors suitable for the present invention include aromatase inhibitors. Examples of aromatase inhibitors include formestane (4-OH androstenedione), exemestane, anastrozole (Appbbeh) and letroxol.

The compounds of the present invention may be administered in combination with an alpha-2-delta ligand. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more alpha-2-delta ligands, in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

Examples of alpha-2-delta ligands for use in the present invention are compounds or their pharmaceutically acceptable salts, disclosed, in general form or specifically, in I8 4024175, in particular gabapentin, EP 641330, in particular pregabalin, ϋδ 5563175, AO-A- 97/33858, AO-A-97/33859, AO-A-99/31057, AO-A-99/31074, AO-A-97/29101, AO-A-02/085839, in particular [(1K, 5K, 68) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid, AO-A-99/31075, in particular 3- (1-aminomethylcyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one and C- [1- (1H-tetrazol-5-ylmethyl) cycloheptyl] methylamine, AO-A-99/21824, in particular (38.48) - (1-aminomethyl-3,4- imethylcyclopentyl) acetic acid, AO-A-01/90052, AO-A-01/28978, in particular (1 α, 3 α, 5 α) (3-aminomethylbicyclo [3.2.0] hept-3yl) acetic acid, EP 0641330, AO-A-98/17627, AO-A-00/76958, in particular (38.5K) -3-aminomethyl-5 methyl-octanoic acid, AO-A-03/082807, in particular (38.5K) -3 -amino-5-methylheptanoic acid, (38.5K) -3-amino-5-methylnonanoic acid and (38.5K) -3-amino-5-methyl-octanoic acid, AO-A-2004/039367, in particular (28 , 48) -4- (3-fluorophenoxymethyl) proline, (28.48) -4- (2,3difluorobenzyl) proline, (28,48) -4- (3-chlorophenoxy) proline and (28,48) -4 - (3-fluorobenzyl) proline, EP 1178034, 1201240, AO-A-99/31074, AO-A-03/000642, AO-A-02/22568, AO-A-02/30871, AO-A-02 / 30881,

AO-A-02/100392, AO-A-02/100347, AO-A-02/42414, AO-A-02/32736 and AO-A-02/28881, all of which are incorporated herein by reference.

Preferred alpha-2-delta ligands for use in the combination of the present invention include gabapentin, pregabalin, [(1K, 5K, 68) -6- (aminomethyl) bicyclo [3.2.0] hept-6-10 014693 yl] acetic acid, 3- (1-aminomethylcyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1Netrazol-5-ylmethyl) cycloheptyl] methylamine, (38.48) - (1-aminomethyl-3, 4-dimethylcyclopentyl) acetic acid, (1 α, 3 α, 5 a) (3-aminomethylbicyclo [3.2.0] hept-3-yl) acetic acid, (38,5Y) -3-aminomethyl-5methyl-octanoic acid, (38 5J) -3-amino-5-methylheptanoic acid, (38.5J) -3-amino-5-methylnonanoic acid, (38.5J ) -3-amino-5-methyl-octanoic acid, (28,48) -4- (3-chlorophenoxy) proline and (28,48) -4- (3-fluorobenzyl) proline or their pharmaceutically acceptable salts.

Other preferred alpha-2-delta ligands for use in the combination of the present invention are (38.5J) -3-amino-5-methyl-octanoic acid, (38.5J) -3-amino-5methylnonanoic acid, (3J, 4J, 5K .) - 3-amino-4,5-dimethylheptanoic acid and (3H, 4H, 5H) -3-amino-4,5-dimethyl octanoic acid and their pharmaceutically acceptable salts. Particularly preferred alpha2-delta ligands for use in the combination of the present invention are selected from gabapentin, pregabalin, (1 α, 3 α, 5 a) (3-aminomethylbicyclo [3.2.0] hept-3-yl) acetic acid, (28, 48) 4- (3-chlorophenoxy) proline and (28.48) -4- (3-fluorobenzyl) proline or their pharmaceutically acceptable salts.

The compounds of the present invention may be administered in combination with an oxytocin receptor antagonist. Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more oxytocin antagonists, in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

Examples of oxytocin receptor antagonists suitable for the present invention are atosiban (EGLPD AB), barusiban (EGLPD AB), TT-235 (No. r1y \ ge51egp Ishuegayu) and A8-602305 (8egopo 8A).

The contents of the published patent applications mentioned above, and in particular the general formulas of the therapeutically active compounds claimed in the claims and the compounds shown in the examples, are fully incorporated into this description by reference.

The compounds of the present invention may also be administered in combination with one or more of the following substances:

(ί) an aromatase inhibitor;

(ίί) an estrogen receptor agonist;

(ΐϊϊ) an angiogenesis inhibitor;

(ίν) an UEOE inhibitor;

(ν) a kinase inhibitor;

(νί) protein pharnesyl transferase inhibitor;

(νίί) an androgen receptor modulator;

(νίίί) androgen receptor agonists;

(ίχ) androgen receptor antagonists;

(x) a prostanoid receptor agonist;

(χί) prostanoid receptor antagonist;

(χί) a prostaglandin synthetase inhibitor;

(χίί) bioflafonoid;

(χίίί) alkylating agent;

(χίν) a microtubule modulator, for example a microtubule stabilizer;

(χν) topoisomerase I inhibitor;

(χνί) metalloprotease inhibitor; or (χνίί) progesterone modulator.

Thus, in another aspect, the invention relates to a pharmaceutical product comprising a progesterone receptor antagonist and one or more of the following:

(ί) an aromatase inhibitor;

(ίί) an estrogen receptor agonist;

(ΐϊϊ) an angiogenesis inhibitor;

(ίν) an UEOE inhibitor;

(ν) a kinase inhibitor;

(νί) protein pharnesyl transferase inhibitor;

(νίί) an androgen receptor modulator;

(νίίί) androgen receptor agonists;

(ίχ) androgen receptor antagonists;

(x) a prostanoid receptor agonist;

(χί) prostanoid receptor antagonist;

(χί) a prostaglandin synthetase inhibitor;

(χίί) bioflafonoid;

(χίίί) alkylating agent;

- 11 014693 (χίν) a microtubule modulator, for example a microtubule stabilizer;

(χν) topoisomerase I inhibitor;

(χνί) metalloprotease inhibitor or (χνίί) progesterone modulator in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.

Typically, the compounds of the invention are administered in the form of a composition in combination with one or more pharmaceutically acceptable excipients. The term excipient is used herein to mean any ingredient other than the compound (s) of the invention. The choice of excipient will largely depend on factors such as the particular route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation are obvious to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in K.etlid1oy'8 Ryagtasei Isa1 8s1eise5, 19 ⁴¹¹ EbShoi (Mask Rybikid Sotrapu, 1995).

The compounds of the invention may be administered orally. Oral administration may include swallowing, such that the compound enters the gastrointestinal tract, and / or buccal, lingual or sublingual administration, by which the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems, such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids or powders; lozenges (including those filled with liquid); chewing gum; gels; fast-dispersing dosage forms; films; suppositories; sprays and buccal / mucoadhesive adhesives.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such compositions can be used as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose) and typically include a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifiers and / or suspending agents . Liquid formulations may also be prepared by reconstituting a solid, for example, from a sachet.

The compounds of the invention can also be used in quick-dissolving, rapidly cleaving dosage forms, such as those described in Exxie Ορίηίοη ίη Tyegarei Ns Railei18, 11 (6), 981-986, Baid Ayeb Syyei (2001).

For dosage forms in the form of tablets, depending on the dose, the drug can comprise from 1 to 80% by weight of the dosage form, usually from 5 to 60% by weight of the dosage form. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, carboxymethyl cellulose sodium salt, carboxyl methyl cellulose calcium salt, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose substituted with lower alkyl, hydroxy-gram-hydroxymyl cellulose-gel gem-garchalcimethylpropyl. Typically, the disintegrant is from 1 to 25% by weight, preferably from 5 to 20% by weight of the dosage form.

Binders are commonly used to impart cohesive properties to a tablet. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. If present, surfactants may comprise from 0.2 to 5% by weight of the tablet and glidants may comprise from 0.2 to 1% by weight of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants typically comprise from 0.25 to 10% by weight, preferably from 0.5 to 3% by weight of a tablet.

Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste maskers.

Examples of tablets contain up to about 80% of the drug, from about 10 to about 90 wt.% Binders, from about 0 to about 85 wt.% Diluents, from about 2 to about 10 wt.% Disintegrant, and from about 0.25 to approximately 10 wt.% lubricants.

The tablet mixes can be pressed directly or by roller to form tablets.

- 12 014693

Mixtures or parts of tablet mixtures may alternatively be prepared by wet, dry or melt granulation, melt freezing or extrusion followed by tabletting. The final composition may include one or more layers and may or may not have a coating; it can also be encapsulated.

The composition of the tablets is discussed in Pbactasei 11ca1 Iokada Rogtk: Tais1k. νοί. 1, b. N. biebstap aib b. Lantai (Magse 1 Jekkeg, Yete ΥογΚ 1980).

Consumable oral films are usually flexible, water-soluble or water-swellable dosage forms in the form of a thin film that can quickly dissolve or adhere to the mucous membrane and typically include a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, viscosity modifier and solvent. Some components of the composition can perform more than one function.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is usually present in the range of 0.01 to 99% by weight, more preferably in the range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivating stimulants, coolants, cosolvents (including oils), emollients, fillers, antifoam agents, surfactants, and taste maskers.

Films in accordance with the invention are usually obtained by drying by evaporation of thin aqueous films deposited on a detachable support substrate or paper. This can be done in an oven or tunnel, usually in a combined coating and drying apparatus, or by freeze-drying or vacuum drying.

Solid compositions for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

Suitable modified release formulations for the purposes of the invention are described in US Pat. No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersion and osmotic, and coated particles, can be found in Pbactasei11ca1 Tepododa Oulite, 25 (2), 1-14, Hugetta e! a1. (2001). The use of chewing gum to provide controlled release is described in SHO 00/35298.

The compounds of the invention may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable agents for parenteral administration include agents for intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrathoracic, intracranial, intramuscular, intravascular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors, and infusion techniques.

Parenteral formulations are usually aqueous solutions that may contain excipients, such as salts, carbohydrates and buffering agents (preferably with a pH of 3 to 9), but for some applications they may be more preferably formulated in a sterile non-aqueous solution or in dried form for use in combination with a suitable carrier, such as sterile pyrogen-free water.

Parenteral formulations can be easily prepared under sterile conditions, for example by lyophilization, using standard pharmaceutical techniques known to those skilled in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by suitable formulation techniques, such as the inclusion of solubility enhancing agents.

Formulations for parenteral administration may be formulated as immediate and / or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds of the invention can be formulated as a suspension or a solid, semi-solid composition or thixotropic liquid for administration to form a depot providing a modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solid forms and suspensions, including drug-loaded microspheres from a copolymer of b1-lactic and glycolic acid (PCL).

The compounds of the invention may also be administered topically, (internally) cutaneous or transdermally through the skin or mucous membranes. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be included - see, for example, 1. Pbmt. 8cp 88 (10), 955-958, Ly Ρίηηίη apb Mogdn (Oslob, 1999).

- 13 014693

Other topical administration agents include electroporation, iontophoresis, phonophoresis, sonophoresis and a microneedle with or without a needle (for example, Po \\ 'bsg | se! ^{| L1} . B | o) ss1 ™, etc.) injection.

Formulations for topical administration may be formulated as immediate and / or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

The compounds of the invention may also be administered intranasally or by inhalation, usually in the form of a dry powder (individually, as a mixture, for example in a dry mixture with lactose, or as a component of a mixture in a particulate composition, for example in a mixture with phospholipids, such as phosphatidylcholine) a powder inhaler, in the form of an aerosol spray from a sealed container, pump, spray, spray (preferably a spray using electrohydrodynamic means to obtain a fine aerosol) or a nebulizer with or without using a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may include a bioadhesive agent, for example chitosan or cyclodextrin.

A sealed container, pump, spray, nebulizer or nebulizer contains a solution or suspension of a compound (s) of the invention, including, for example, ethanol, an aqueous ethanol solution or a suitable alternative means for dispersing, solubilizing or prolonged release of the active substance, propellant (s) ) as a solvent and an additional surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

Prior to use in the composition in the form of a dry powder or suspension, the drug product is ground to a size suitable for delivery by inhalation (usually less than 5 microns). This can be done by any suitable grinding method, such as grinding a spiral jet, grinding a fluidized bed jet, treating a supercritical fluid to produce nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyl methylcellulose), vials and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention, a suitable powder base such as lactose or starch, and a modifier of characteristics such like 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution composition for use in an atomizer using electrohydrodynamic agents to produce a fine aerosol may contain from 1 μg to 20 mg of the compound of the invention per actuation, and the volume per actuation can vary from 1 to 100 µl. A typical composition may include a compound of formula (I), propylene glycol, sterilized water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to the compositions of the invention for inhalation / intranasal administration.

Compositions for inhalation / intranasal administration can be formulated as compositions for immediate and / or modified release, for example, using PCBA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is the traditional suppository base, but various suitable alternatives can be used.

Formulations for rectal / vaginal administration may be formulated as formulations for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

The compounds of the invention can be combined with soluble macromolecular substances, such as cyclodextrin and its suitable derivatives, or polyethylene, glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of these routes of administration.

It has been found that drug-cyclodextrin complexes, for example, are generally suitable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with a drug, cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. Typically, alpha, beta, and gamma cyclodextrins are used for these purposes, examples of which can be found in international patent applications XVO 91/11172,

- 14 014693

94/02518 and 98/55148.

Since it is desirable to administer a combination of active compounds, for example, to treat a particular disease or condition, within the framework of the present invention, two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may be combined in the form of a kit suitable for co-administration these compositions.

Thus, the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately storing said compositions, such as a container, a divided balloon or a divided foil bag . An example of such a kit is a conventional blister pack used to store tablets, capsules, etc.

The kit of the invention is particularly suitable for administering various dosage forms, for example, oral and parenteral, for administering individual compositions at different intervals or for titrating the individual compositions with respect to each other. To provide the complex, the kit usually includes directions for administration and can be supplied with so-called instructions.

For administration to humans, the total daily dose of the compounds of the invention is usually in the range of <1 to 1000 mg, but, of course, depends on the route of administration. For example, oral administration may require a full daily dose of <1 to 1000 mg, while intravenous administration may require only <1 to 500 mg. The full daily dose may be administered in a single dose or in divided doses and, at the discretion of the physician, may go beyond the typical range indicated here.

These doses are based on the average person having a body weight of about 60 to 70 kg. The doctor will easily determine the dose for patients whose body weight is outside this range, such as children and the elderly.

For the purposes of the invention, the terms “treatment” and “treatment” mean relieve symptoms, eliminate the cause, temporarily or permanently, or prevent or slow the onset of symptoms. The term treatment includes alleviating, eliminating the cause (temporarily or permanently) or preventing the symptoms and disorders associated with endometriosis and / or uterine leiomyoma. Treatment can be prophylactic treatment, as well as treatment at the onset of symptoms.

The compounds of the present invention can be tested in the screenings set forth below.

1.0. Ш νίίτο functional test for antagonism to the progesterone receptor (PK).

The antagonism test for PK is based on the well-known effect of modulating the expression of alkaline phosphatase (AR) in human breast cancer cells Τ47Ό (Veyek Ό.Ρ. s1 a1. (1993). С cAMP idiaid ραΐΗ ^ αλ'δ., Proc. No. 111. Ass. 8s1 I8A, 90, 4441-4445; Reikots e1 a1. (2002) No. Furniture.Set.Lsy., 12, 3487-3490; 2yayd e1 a1. (2002a) 6-Agu1-1,4-bShubgo-bs7o b 1,3 okh / t-2-og1sk: and bt1 s1akk o £ roki !, xksyus, aib ogra11u asyus ioikkgo1ba1 rtodekkgois hessrYug ayadoηΐδίδ, 1 oigia1 o £ Msbkta1 Syst1kyu, 45, 4379-4382; 2yayd e1 a1. (2003) No. ts1 6-ay1-1,4-b1yubgoi7o b okh / ts ^ -Search for akkry, ksksyus, aib ogra11u asyusgoyskogo1 Vyuogdats & Msbkta1 Syetkyu bsNegk, 13, 1313-1316; 2yayd e1 a1. (2002b) RoiSgIoiky1b1 rgodsk1sgois hessyyu adoshyk: kuyskk aib 8AK ktbu ost6bgtbgtbgtbg77 2yaid, Ζ. e1 a1. (2000) Shungo syagaysp / ayoi o £ й т с с д д ис ис ис: а а: ис у ро ро 1 И И иб иб к 1 сс сс 11 ус ус год год год год год год год. 81sgo1bq 65, 637-643). In the presence of progesterone, endogenous expression of AR is induced in Τ47Ό cells and is inhibited by compounds with antagonistic activity to PK. In the absence of progesterone, any agonist activity is also observed as induction of AR activity. When conducting the test in two formats (+/- progesterone (P4)), compounds behaving as antagonists, agonists or partial agonists of the Republic of Kazakhstan can be identified.

- 15 014693

The materials necessary for the growth of Τ47Ό cells and the progesterone-induced AR test are shown in table. one.

Table 1

Reagent Provider Catalog Number Human breast cancer cells Τ4 7ϋ AtegFsap Mzzie siFsige sofFesbFopz; ΗΐΑρ: //ig.abss.ogd/ NTV-133 Dimethyl sulfoxide (DMSO) WFdta B2650 Dulbecco Modified Needle Medium (ϋΜΕΜ) Sfso 21969-035 ΏΜΕΜ without phenol red Sfso 31053-028 B-C1ibatah, 200 mm Sfso 35050-038 Charcoal-purified fetal calf serum - (SZ-ESZ) Coferter Saline Phosphate Buffer (PBP) Sfso 14190-094 Emboionic Bovine Serum (EVZ) 3 ί one hundred E-7524 ΒΏ Sgeab Ezsare ZEAR SietItgezepsepsse WebesSFop kFS Gfz K2041-1 Progesterone (P4) WFdta P-6149 R1igopfs-E127 Mo1essi1ag Prgoes P6867 Κϋ48 6 (Mifepristone) WFdta M-8046

Test media (agonistic format): ΌΜΕΜ without phenol red + 5% C8-HS8 + 2 mM O1i (atax.

Test media (antagonistic format): ΌΜΕΜ without phenol red + 5% C8-HS8 + 2 mM C1i (atax + 10 nM P4.

Briefly, Τ47Ό cells are grown in propagation ΌΜΕΜ GB8 + 10% + 2 mM S1i (amax at 37 ° C / 5% CO _2. At confluence 80-90% medium exchange on ΌΜΕΜ without phenol red + 5% S8GS8 (dough Wednesday ) and cultured for another 24 hours at 37 ° C / 5% CO ₂ .4747 cells were seeded at a density of 2.5 x ^{10 4} cells / well in 100 ml of test medium in 96-well test plates in 3 copies for each condition. 5 points for construction ₅₀ in one compound curve is equivalent to 36 wells (wells 2h18, ± P4). These plates are then cultured for 24 hours at 37 ° C / 5% _CO2, leaving the outside wells of the control adding 200 ml RV8.

mm stock solution of the compounds obtained in DMSO (stored at -20 ° C in 10 ml aliquots). 10 mM stock solution of KI486 in DMSO is used as a standard pure RK antagonist. Test compounds or a mixture of 0.05% pluronic acid in PB8 ± 10 nM P4 are added to the test medium to obtain a final concentration of 20 μM (i.e. 10 μl of 10 mM stock solution per 5 μl of test medium ± 10 nM P4). Samples were thoroughly mixed and serial dilutions of compounds from 10 μM to 0.1 nM in 96-well plates were prepared as follows.

External wells are left to control. Test medium (225 μl) was added to one half of the plate (-P4), rows 3-8, and test medium + 10 nM P4 was added to the other half of the tablet. To row 2, 250 μl of the highest concentration of compound (20 μM ± 10 nM P4) was added. 25 μl of a 20 mM stock solution is removed from row 2 and added to 225 μl of test medium ± 10 nM P4 in row 3 and mixed thoroughly. This process is repeated throughout the tablet to row 7, obtaining successive dilutions. The control support was rectified so that the content of DMSO was 0.1% (i.e., 20 μl per 10 ml of test medium ± 10 nM P4 to obtain a dimethyl sulfoxide concentration of 0.2%, 250 μl, in row 8).

- 16 014693

BUT IN FROM E g from n one 2 20 μm - P4 3 2 μm 4 200 nM 5 20 nM H 20 nM ⁷ <; 6 2 nM 7 0.2 nM 8 0 nM media nine

100 μl of reagent from the dilution plates was transferred to the appropriate well containing Τ47Ό cells in 100 μl of test medium, resulting in a final concentration of 10 μM to 0.1 nM compound (5 nM P4 antagonistic format). Cells are incubated for 20 hours at 37 ° C / 5% CO ₂ , then the media is removed, the cells are washed with PB8 (200 μl) and lysed, placing the cells at -80 ° C for 15 min and thawing at room temperature. Freeze-thaw lysis is repeated, then PB8 (50 μl) is added to each well. After 5 minutes, 30 μl of a chemiluminescent solution of the C8RE substrate (final concentration of 0.06125 mmol, 1.25 mmol of the solution x20 dilutions with chemiluminescence enhancer Ogea! Ezsare 8ELP Sjettezetsepsu Pepten) is added to each well and mixed. The plates were incubated for 30 minutes at room temperature and the luminescence was measured on a luminometer (UGSTOK, ^ a11ac).

The test is carried out three times, in an agonistic format (in the absence of exogenous P4), with the construction of a sigmoid curve of the results, expressed as induction by the test compounds of alkaline phosphatase (luminescence, arbitrary units or percentage with a maximum progesterone response, taken as 100%). In this format, the EC ₅₀ value is defined as the concentration of the drug required to obtain a 50% induction of AR activity compared to 5 nM individually. Compounds with agonism or partial agonism, i.e. with the induction of AR activity, which is submaximal with respect to the induced P4, is thus excluded. In an antagonistic format (5 nM P4), a curve is constructed of the results expressed as inhibition of alkaline phosphatase by test compounds. In this format, the TC ₅₀ value is defined as the concentration of the drug required to obtain a 50% inhibition of AR activity compared to 5 nM individually. With respect to the compounds illustrated herein, TC ₅₀ values are less than 5 μM. In a preferred embodiment, the TC ₅₀ value is less than 500 nM. In a more preferred embodiment, the GS ₅₀ is less than 50 nM.

2.0. S νίΐΐΌ functional test of glucocorticoid activity (OK).

In this test, the 8 ^ 1353 cell line stably transfected with the full-length OK construct and the mouse breast tumor luciferase (Euc) reporter gene (MMTU) are used to conduct the ίη νίΐΐΌ functional test of glucocorticoid activity. The materials necessary for the growth of 8 ^ 1353-MMTU-OK-Uis cells and the test are shown below or are presented in table. one.

Cells 8 \ 1353-MMTU-OK-Eis grown in EMEM containing 10% EB8, 2 mM d1i! Atax and O418 (0.5 mg / ml, O1bco catalog number 10131-027) are seeded at a density of 0, 5x10 ⁴ cells / well (384-well tissue culture plates with black walls and a transparent bottom (Ogeteg catalog number 781091)) in 30 ml using a Mi1bgor micropipette and incubated at 37 ° C, 5% CO ₂ overnight. The media are replaced with test media (30 μl; EMEM-phenol red containing 1 mg / L insulin, 2 g / L lactalbumin hydrolyzate and ascorbate (0.5 mg / L) added immediately before use) at least 4 hours before introduction. The test is carried out in two formats, an antagonistic format in which test compounds are evaluated for their ability to block the effect of 20 nM dexamethasone on luciferase activity, and an agonistic format. A separate 384 well plate is used to evaluate compounds in both formats.

The Oepe818 robot is used to dilute and extract 1/2 1 unit (11 points) dose response (starting from the final 1 μM; 16 compounds / 384-well plate) from a 96-well plate containing 4 mM stock concentrations of test compounds. Test compounds are diluted in

- 17 014693 test medium + 3.75% DMSO or a mixture of 0.05% pluronic acid in PB8. Dexamethasone and Κϋ-486 (final concentration of 1 μM) as a positive control are obtained from concentrated stock solutions. MLTK1X P1a1et1e is used to transfer 10 μl of the diluted compound to the plates and either 10 μl of medium or standards so that the final sample volume is 50 μl. Cells and compounds are incubated at 37 ° C, 5% CO ₂ overnight. The reagent 81eabu-O1o 1d1sIl1e (Rgoted sa! Oo. E2520) was resuspended and 30 μl per well was added, left in the dark for 5 minutes and then the plate was read on a luminescence counter ^ a11ac. All data items are measured twice.

In a agonistic format, a sigmoid curve of the results expressed as induction of luciferase compounds tested (% of the maximal response of dexamethasone) is built, and the EC ₅₀ value is determined. In an antagonistic format, the results are expressed as inhibition of luciferase by test compounds and determine the value of 1C ₅₀ .

3.0 1and νί \ Ό study on progesterone receptor antagonism using the MacPhail test.

A classic quantitative study of progestogenic activity is the MacPhail test, conducted on an immature rabbit (McRap, 1934).

All compounds according to formula (I) can be obtained by the usual methods, such as the procedures described in the general methods presented below, or by specific methods described in the examples section, or similar methods. The present invention also encompasses one or more of these processes for preparing compounds of formula (I) in addition to any new intermediates used therein.

In the following general methods, KZ-K ⁸ , X, Υ, and a have the meanings defined for the compound of formula (I) unless otherwise indicated.

In Scheme 1 below, compounds of formula (I) can be prepared by oxidizing a compound of formula (II). Oxidation occurs through sulfoxide (ya) (a = 1) to produce sulfone (b) (a = 2)

Many suitable oxidizing agents and oxidation conditions are available in the scientific literature for the conversion of sulfides to sulfoxides and sulfones. In particular, a preferred method is to react with Ohioie® in a solvent mixture, such as a mixture of methanol and water, at temperatures from ambient temperature to boiling point.

In Scheme 2 below, sulfides of formula (II) can be prepared by alkylation of pyrazoles of formula (III) using compounds of formula (IV) (where b ¹ is a leaving group, such as chlorine), and a suitable base, such as potassium tert-butoxide, in a suitable solvent, such as dimethoxyethane, at temperatures from ambient temperature to boiling point.

- 18 014693

(V) (VI)

Scheme 2

Alternatively, sulfides of formula (II) can be prepared from compounds of formula (VI), where L ² is a leaving group, such as chlorine, by reaction with a thiolate salt of formula K ² 3M ⁺ , where M ⁺ is a cation, such as Wa, K, or Cu, in a suitable solvent such as 1,4-dioxane, dimethylformamide or tetrahydrofuran. Compounds of formula (IV) can be prepared by activating the hydroxyl of compounds of formula (V) to form a leaving group L ² . Preferably, when b ² is chlorine, this can be done using thionyl chloride in dichloromethane. Compounds of formula (V) can be prepared by reacting compounds of formula (III) with a formaldehyde source such as aqueous formaldehyde. When K / ^ K ³ in the compounds of formula (III), then the resulting compounds of formula (II), (V) and (VI) can exist as regioisomers with transposed K ¹ and K ³ , which can be separated.

In Scheme 3 below, compounds of formula (III) in which Υ is O can be prepared by condensation of a compound of formula (VII) with hydrazine or a salt or hydrate thereof, if necessary in the presence of an acid or a base. The base is preferably a tertiary amine base such as triethylamine. The acid is preferably acetic acid. In a typical procedure, a solution of the compound of formula (VII) in a suitable solvent, such as ethanol, is treated with hydrazine or a salt or hydrate thereof, and, if used, with a suitable acid or base, at a temperature from room temperature to the boiling point of the solvent. In a preferred procedure, the reaction mixture is refluxed in ethanol and acetic acid.

Compounds of formula (VII) can be prepared by reacting compounds of formula (VIII) with compounds of formula (X) and a suitable base such as cesium carbonate in a solvent such as acetone. Compounds of formula (VIII) are commercially available or can be prepared by reacting a compound of formula (IX) with a chlorinating reagent. In a typical procedure, a cooled solution of the compound of formula (IV) in a suitable solvent such as acetonitrile is treated first with tetrabutylammonium bromide and chlorotrimethylsilane and then with dry dimethyl sulfoxide.

Functional equivalents of the compounds of formula (VII) may also be used in this reaction. These include compounds of formula (XI) or (XII) in which L ³ is a suitable leaving group; -I preferably (C1-C ₆ -alkyl) _2, more preferably -I _{(CH3) 2.}

- 19 014693

Thus, a compound of formula (III) can be prepared by condensing a compound of formula (XI) or (XII) with hydrazine or a salt or hydrate thereof, optionally in the presence of an acid or a base (the base being preferably a tertiary amine base such as triethylamine, and the acid is preferably acetic acid). In a typical procedure, a solution of a compound of formula (XI) or (XII) in a suitable solvent (such as ethanol) is treated with hydrazine or a salt or hydrate thereof and, if used, with a suitable acid or base, at a temperature from room temperature to the boiling point of the solvent. In a preferred procedure, the reaction mixture is refluxed. Compounds of formula (XI) or (XII) are particularly suitable for the synthesis of compounds of formula (I), in which K ¹ or K ³ , respectively, represent N.

Compounds of formula (XI) in which K ¹ is H and compounds of formula (XII) in which K ³ is H and b ³ is dimethylamino can be prepared by reacting a compound of formula (XIII) below with dimethylformamide dimethyl acetal temperature, preferably at about 100 ° C.

Y ^ ^{1 or 3} ' ⁰

Compounds of formula (XIII) are commercially available or can be prepared by reacting a compound of formula (XIV) with phenol of formula (X):

VgSN ₂ SOK ^{(1 or 3)} (XIV)

In a typical procedure, a solution of a compound of formula (XIV) in a suitable solvent, such as acetone, is treated with a suitable base, such as cesium carbonate, and a compound of formula (X). In a preferred procedure, the reaction mixture is heated, for example, under reflux. If necessary, a nucleophilic catalyst such as sodium iodide or tetrabutylammonium iodide may be added.

In Scheme 4 below, compounds of formula (III) in which Υ is CH ₂ can be prepared by a method similar to that described in scheme 3 by condensation of a compound of formula (XV) with hydrazine. Compounds of formula (XV) can be prepared by alkylation of compounds of formula (IX) using compounds of formula (XVI), where b ⁴ is a leaving group, such as chloro, bromo or iodo, with a suitable base, such as sodium hydride or potassium tert-butoxide in a suitable solvent, such as tetrahydrofuran or 2-butanone, at temperatures from room temperature to the boiling point of the solvent.

(Xvi)

Scheme 4

One skilled in the art will recognize that in many cases the compounds of formula (I) can be converted to other compounds of formula (I) by functional group transformations.

- 20 014693

Thus. according to a further aspect, the invention relates to a method for producing compounds of formula (I). in which a = 1. which includes the oxidation of the compounds of formula (II):

(Ii)

G in which K ¹ -K ⁸ . X and Υ have the meanings defined above.

Besides. The invention relates to a method for producing compounds of formula (I). in which a = 2.

in which KZ-K ⁸ . X and Υ have the meanings defined above.

Besides. The invention relates to a method for producing compounds of formula (I). in which a = 2. which includes oxidizing a compound of formula (S)

(1a) in which K ¹ -K ⁸ . X and Υ have the meanings defined above.

Also included in the scope of the invention are intermediates of formula (II). as defined above. all their salts. solvates and complexes and all solvates and complexes of their salts. as defined above for compounds of formula (I). The invention includes all polymorphs of these compounds and their crystalline forms.

Upon receipt of the compounds of formula (I) in accordance with the invention, one of ordinary skill in the art can select the form of the compound of formula (II) using routine methods. which will provide the best combination of relevant features. Such characteristics include melting point. solubility. ease of use and output intermediate form and as a result lightness. with which the product can be cleaned after isolation.

The compounds of the invention may have an advantage in that regard. that they are more powerful. have a longer duration of action. have a wider range of activity. are more stable. have fewer side effects or are more selective. or have other more useful properties. than prior art compounds.

Thus. The invention relates to:

(ΐ) a compound of formula (I) or a pharmaceutically acceptable derivative thereof;

(ΐΐ) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable derivative thereof;

(ϊϋ) to the pharmaceutical composition. comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with pharmaceutically acceptable excipients. diluent or carrier;

(ΐν) a compound of formula (I) or a pharmaceutically acceptable derivative or composition thereof for use as a medicine;

(ν) the use of a compound of formula (I) or a pharmaceutically acceptable derivative or composition thereof for the manufacture of a medicament for the treatment of endometriosis. uterine fibroids (leiomyomatous lesions). menorrhagia. adenomyosis. primary and secondary dysmenorrhea (including symptoms of dyspareunia. difficult bowel movements and chronic pelvic pain). chronic pelvic pain syndrome;

(νΐ) for use as in (ν). where the disease or disorder is endometriosis and / or uterine fibroids (leiomyomatous lesions);

(νΐΐ) to a method for treating a mammal for treating endometriosis. uterine fibroids (leiomyomatous lesions). menorrhagia. adenomyosis. primary and secondary dysmenorrhea (including symptoms of dyspareunia. difficult bowel movements and chronic pelvic pain). chronic pelvic pain syndrome. comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative or composition thereof;

(νΐΐΐ) to the method as in (νΐΐ). where the disease or disorder is endometriosis and / or uterine fibroids (leiomyomatous lesions);

- 21 014693 (ίχ) to the intermediate compounds of formulas (II).

The following preparation examples and examples illustrate the preparation of compounds of formula (I).

The ¹ H spectra ^of nuclear magnetic resonance (NMR) were in all cases compatible with the proposed structures. Typical chemical shifts (δ) are given in parts per million in the direction of the weak field from tetramethylsilane using the usual abbreviations for the main peaks: for example, 8, singlet; b, doublet; ΐ, triplet; q, quartet; t, multiplet; Bg broadened.

The following abbreviations were used everywhere:

NYaM8 - high resolution mass spectrometry;

LUM8 - low resolution mass spectrometry;

HPLC - high performance liquid chromatography;

PoE is the nuclear Overhauser effect;

t. pl. - the melting temperature;

СОС1 ₃ - deuterochloroform;

E ₆ -DMSO - deuterodimethyl sulfoxide;

ί.Ό ₃ ΟΟ - deuteromethanol

The preparation examples and examples that follow illustrate the invention, but in no way limit the invention. All starting materials are commercially available or described in the literature. All temperatures are given in ° C. Flash column chromatography was performed using Megsk 8111ca de1 60 (9385). Thin layer chromatography (TLC) was performed on plates with Megsk 8111ca de1 60 (5729). Κι denotes the distance traveled by the compound divided by the distance traveled by the solvent on the TLC tablet. The melting point was determined using a Ca11epcatr MRE350 instrument and was not corrected. NMR was performed using a 400 MHz Uapap Ipbu Show NMR spectrometer or a 400 MHz Uapap Meggig NMR spectrometer. Mass spectroscopy was performed using a separate four-pole electrospray mass spectrometer Rschdap No. \ schaog or a mass spectrometer NPShchap aTSa ARSk

If it is indicated that the compounds were prepared as described in an earlier production example or example, one skilled in the art will recognize that the reaction time, the number of equivalents of the reactants and the reaction temperature can be changed for each specific reaction, and that it may, however, be necessary or desirable to use other processing or cleaning conditions.

Preparation 1. 1,3-Dicyclopropylpropane-1,3-dione.

Methylcyclopropanecarboxylate (20.2 ml, 286.3 mmol) was added to a stirred solution of 1-cyclopropylethanone (9 ml, 152.4 mmol) in dimethyl sulfoxide (25 ml). Sodium methylate powder (10.8 g, 200 mmol) was added and the reaction mixture was stirred at 55 ° C for 8 hours. The reaction mixture was cooled, diluted with toluene, neutralized with 6 M hydrochloric acid, and then extracted with toluene. The combined extracts were washed with sodium carbonate, dried over magnesium sulfate and evaporated in vacuo to give the desired compound (14.9 g, 78%) as a 2: 1 mixture of enol: ketone form.

Ή NMR (SPS1 ₃ , 400 MHz): δ = 0.79-0.87 (m, 4H), 0.98-1.01 (m, 4H), 1.46-1.51 (m, 2H- enol), 1.93-1.97 (m, 2H-ketone), 3.70 (s, 2H-ketone), 5.65 (s, 1H-enol); LAMZ: ARS! ': T / ζ 153 [MH ⁺ ]; ARSG: t / ζ 151 [M-H] ^- .

Getting 2. 3-Oxobutanoic acid.

Sodium hydroxide (37.9 g, 947 mmol) was dissolved in water (770 ml) and was added to a solution of 3-oxobutanoic acid methyl ester (100 g, 861 mmol) at room temperature over 20 minutes. The reaction mixture was stirred for 18 hours, then quenched with ammonium sulfate (700 g) and slowly acidified with a solution of concentrated hydrochloric acid (21.5 ml) in water (250 ml) while cooling on ice. The reaction mixture was extracted with diethyl ether (6x200 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound (58.2 g, 60%) in the form of a light yellow oil, which was a mixture of ketone: enol tautomers .

Ή NMR (400 MHz, COC1 ₃ ): δ = 2.00 (s, 3H-enol), 2.30 (s, 3H-ketone), 3.51 (s, 2H-ketone), 5.02 (s , 1 H-enol).

Getting 3. 1-Cyclopropyl-1,3-butanedione.

Magnesium shavings (3.04 g, 125 mmol) suspended in methanol (145 ml) were heated with

- 22 014693 by a reflux condenser in a nitrogen atmosphere for 1 h, then it was cooled to room temperature and β-keto-acid was added dropwise while cooling on ice from Preparation 2 (25.5 g, 250 mmol) dissolved in methanol (25 ml ) The reaction mixture was stirred for 1 h at room temperature, and then the solvent was removed under reduced pressure to obtain a magnesium salt of the acid. Meanwhile, cyclopropanecarboxylic acid (9.91 ml, 125 mmol) was dissolved in dimethylformamide (200 ml). Then, carbonyldiimidazole (22.4 g, 138 mmol) was added portionwise in a nitrogen atmosphere at 0 ° C. This reaction mixture was stirred for 1.5 hours, and then the magnesium salt described above was added at 0 ° C. in the form of a solution in Ν, Ν-dimethylformamide (100 ml). The reaction mixture was stirred at room temperature for 92 hours and then poured into a 2 M aqueous hydrochloric acid solution (85 ml), after which it was diluted with water (170 ml). The mixture was extracted with diethyl ether (6x200 ml) and the combined organic extracts were washed with brine (3x200 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluting with a pentane: diethyl ether mixture (100: 0, then 90:10, then 80:20, v / v) to give the desired compound (7.39 g, 24%) as a yellow oil .

¹ H NMR (400 MHz, SES1e): δ = 0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H) 2.00 (s, 3H); ΙΉΜ8 (electrospray): t / ζ 149 [ΜΝα ⁺ ].

Preparation 4. 2-Chloro-1,3-dicyclopropyl-1,3-propanedione.

Chlorotrimethylsilane (36 ml, 296 mmol) was added dropwise to a stirred solution of tetrabutylammonium bromide (1.54 g, 5 mmol) in dry acetonitrile (100 ml) at room temperature under a nitrogen atmosphere. The resulting solution was cooled on ice and diketone was added dropwise from Preparation 1 (15 g, 98.7 mmol) in the form of a solution in acetonitrile (30 ml), then dry dimethyl sulfoxide (20 ml, 296 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 hours. The mixture was diluted with water, stirred for 10 minutes and then extracted with diethyl ether (50 ml). The layers were separated and the aqueous layer was again extracted with diethyl ether. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a pentane: diethyl ether mixture (20: 1, v / v), to obtain the target compound as a 2: 7 mixture of ketone: enol tautomers (12.1 g, 66%).

¹ H NMR (400 MHz, SES1e): δ = 1.01-1.07 (m, 4H), 1.16-1.21 (m, 4H), 2.23-2.28 (m, 2H- ketone), 2.39-2.44 (m, 2H-enol), 5.07 (s, 1H-ketone); LKM8: APC1 ⁺ : t / ζ 187 [MH ⁺ ]; APC1 ^- : t / ζ 185 [M-H] ^- .

Receive 5-8.

Compounds of the following preparations having the general formula

obtained by a method similar to that described in obtaining 4, using a suitable diketone as starting material ._____________________________________________________________________

Receiving No. KZ, K 4 Analysis Data 5 Me, srg Ή NMR (400 MHz, CPC1 ₃ ): 5 = 1.01-1.04 (m, 2H), 1.14-1.20 (i, 2H), 2.27 (s, 3H), 2.43 (m, 1H); LKMZ: APC1 ⁺ : t / ζ 161 [MH ⁺ ]; ARC1 ”t / ζ 159 [M-H] ' ^? (62% yield). b EG, EU Ή NMR (400 MHz, COC1 ₃ ): δ = 1.12 (τ, 6H), 2.59 (q, 4H), 4.77 (s, 0.2H, proton). 15.50 (p. 0.8H. Enol): GKMZ (thermal spraying): t / ζ 18 0 [ΜΝΗ4 ⁺ ]; (15% yield). 7 GVI, bVi Ή NMR (400 MHz, COC1 ₃ ): 5 = 1.25 (br s, 18H), 5.65 (s, 1H); LNMZ ARS1 't / ζ 217 [M-H]'; (95% yield). 8 Me bb ^X H NMR (400 MHz, COC1 ₃ ): 5 = 1.25 (br s, 9H), 2.25 (s, 3H), 5.65 (s, 1H); LKMZ: APC1 ⁺ : t / ζ 177 [MH ⁺ ]; APC1 ~ t / ζ 159 [M-H] '; (70% yield).

- 23 014693

Preparation 9.4- (3,5-Dicyclopropyl-1H-pyrazol-4-yloxy) benzonitrile.

Stage 1

A mixture of chlordiketone from Preparation 4 (48.2 g, 258 mmol), 4-cyanophenol (37 g, 310 mmol), cesium carbonate (101 g, 310 mmol) and acetone (1200 ml) was heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned between diethyl ether (1000 ml) and water (300 ml). The layers were separated and the organic layer was washed with water (2x500 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with a pentane: dichloromethane mixture in a ratio of 1: 1 before starting the elution of the product and then in a ratio of 1: 2 to complete the elution. The solvent was evaporated, yielding the intermediate 4- (1-cyclopropanecarbonyl 2-cyclopropyl-2-oxoethoxy) benzonitrile in the form of a solid (44.1 g) (note: this intermediate can be purified by silica gel chromatography eluting with ethyl acetate: pentane or used on stage 2 in the form of a crude diketone).

Stage 2

4- (1-Cyclopropanecarbonyl-2-cyclopropyl-2-oxoethoxy) benzonitrile (44 g, 162 mmol) was dissolved in acetic acid (500 ml). At room temperature, a solution of hydrazine hydrate (8.7 ml, 179 mmol) in ethanol (50 ml) was added and the reaction mixture was heated at 90 ° C for approximately 3 hours. The solvents were evaporated under reduced pressure, the residues were partitioned between diethyl ether (600 ml) and a dilute aqueous solution of ammonium hydroxide (25 ml of concentrated ammonium hydroxide in 500 ml of water) and the layers were separated. The aqueous layer was extracted with diethyl ether (3x200 ml) and the combined organic layers were washed with water (2x50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solid was suspended in diisopropyl ether (50 ml), filtered and washed with diisopropyl ether (2x30 ml) and pentane (2x100 ml) to give the desired compound (39.5 g, 58%) as a colorless solid.

¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.76-0.81 (m, 8H), 1.59-1.65 (m, 2H), 7.01 (d, 2H), 7, 60 (d, 2H); LKM8: ARSG: t / ζ 266 [MH ⁺ ]; ARSG: t / ζ 264 [M-H] ^- .

Receive 10-24.

Compounds of the general formula given above were prepared using a method similar to that described in Preparation 9, using as the starting materials chlorodiketone from Preparation 4 and a suitable phenol (Ar ₁ 0H, available commercially or from Preparation 42 or 45).

- 24 014693

Getting

AG1 Analysis Data

^X H-NMR (400 MHz, 0ϋ01 ₃ ): 5 = 0.75-0.86 (m, 8H), 1.59-1, 66 (m, 2H), 2.51 (s, 3H), 6 81 (d, 1H); 6.87 (s, 1H); 7.52 (d, 1H); NNMZ: APC1 ⁺ : t / ζ 280 [MH ⁺ ]; ARS1 ":

t / ζ 278 [M – H] ~ (4 5% yield)

Ή-NMR (400 MHz, СОС1 ₃ ): 5 = 0.75-0.81 (m, о and \ in / _g

6, 67 [MH ⁺ ];

Ί / C Η _ 1 / C / C X / and V “X / and V (s,

ARS1 ":

O / I r g APC1 ⁺ :

/ t / ζ / С τ τ \ in; _g

294 t / ζ

292 [M-H] ', (55% yield) ____________________________________ ^X H-NMR (400 MHz, COS1 ₃ ): 5 = 0.76-0.79 (m,

4H), 0.82-0, 85 (m, 4H), 1.59-1, 64 (m, 2H), 6.93 (d, 1H), 7.07 (s, 1H), 7.55 (broad s, 1H); 7.60 (d, 1H); BIMZ: APC1 ⁺ :

t / ζ 300 [MH ⁺ ]; APC1 ”: t / ζ 298 [M-H], (50% yield) __________________________________ ^X H-NMR (400 MHz, COS1 ₃ ): 5 = 0.76-0.87 (m,

8H), 1.63 (m, 2H), 6.77 (dts, 1H), 6.85 (dd, 1H), 7.55 (dd, 1H); LKMZ: ARS1 ⁺ :

t / ζ 284 [MH ⁺ ]; APC1 ~: t / ζ 282 [M-H] ^- , (4 8% yield) __________________________________ ^X H-NMR (400 MHz, СОС1 ₃ ): 5 = 0.76-0.85 (m, 8Н), 1, 63 (m, 2H), 6.83 (d, 1H), 7.49 (dd, 1H), 7.74 (d, 1H); GR, M3: APC1 ⁺ : t / ζ 300 [MH ⁺ ]; APC1 ^- : t / ζ 298 [M-H], (35% yield) ^X H-NMR (400 MHz, COC1 ₃ ): 5 = 0.74-0.85 (m,

8H), 1.63 (m, 2H), 6.85 (t, 1H), 7.40 (d, 1H), 7.47 (dd, 1H); LRMZ: ARSG: t / ζ 284 [MH ⁺ ]; APC1: t / ζ 282 [M-H], (38% yield) _____________________________________ ^X H-NMR (400 MHz, COS1 ₃ ): 5 = 0.77-0.81 (m,

8H), 1.64 (m, 2H), 3.99 (s, 3H), 6.75 (d, 1H), 7.20 (m, 2H); LKMZ: APC1 ⁺ : t / ζ

296 [MH ⁺ ], (25% yield) _____________________

Я-NMR (400 MHz, СОС1 ₃ ): 5 = 0.73-0.79 (m, 8Н), 1.63 (m, 2Н), 6.72 (d, 1Н), 7.67 (τ, 2H), 7.76 (dd, 2H), 8.22 (d, 1H),

8.50 (d, 1H); LKMZ: APC1 ⁺ : t / ζ 316 [MH ⁺ ]; APC1 ”: t / ζ 314 [M-H] ^- , (25% yield) __________________________________________ ^X H-NMR (400 MHz, ά-6 acetone): 5 = 0.720.80 (m, 8H), 1.69 (m , 2H), 2.81 (s, 1H), 6.95 (d, 1H), 7.79 (dd, 1H), 8.20 (d, 1H), 8.93 (dd, 1.76 Hz) , 1H); 9.13 (dd, 1H); GKMZ: ARS1 ⁺ : t / ζ 317 [MH ⁺ ];

APC1 ^- : t / ζ 315 [M-H] ^- , (22% yield)

- 25 014693

nineteen ^X H-NMR (400 MHz, COC1 ₃ ): 6 = 0.77 (d, 8H), 1.63 (m, 2H), 6.66 (d, 1H), 7.62 (t, 1H), 7.79 (m, 1H), 8.20 (d, 1H), 8.41 (m, 1H), 8.72 (d, 1H); LKMZ: APC1 ⁺ : t / ζ 292 [MH ⁺ ]; APC1 ': t / ζ 290 [M-H]', (35% yield) twenty y / ^X H-NMR (400 MHz, COC1 ₃ ): 6 = 0.74-0.85 (m, 8H), 1.63 (m, 2H), 6.7-6.8 (m, 2H), 7 30 (d, 1H); LKM8: APC1 ⁺ : t / ζ 293 [MH ⁺ ]; APC1 ': t / ζ 291 [M-H]', (43% yield) 21 ^X H-NMR (400 MHz, COC1 ₃ ): δ = 0.74-0.85 (m, 8H), 1.63 (m, 2H), 6.63 (m, 1H), 6, 75 (m , 1H); 7.07 (m, 1H); NNMZ: APC1 ⁺ : t / ζ 277 [MH ⁺ ]; APC1 ': t / ζ 275 [M-H]', (46% yield) 22 UU E ^X H-NMR (400 MHz, COC1 ₃ ): 6 = 0.75-0.86 (m, 8H), 1.64 (m, 2H), 6.57 (m, 2H), 8.96 (s , 1H); KMZ: APC1 +: t / ζ 295 [MH +]; APC1-: t / ζ 293 [M-H] -, (40% yield) 23 R ^X H-NMR (400 MHz, COC1 ₃ ): δ = 0.74-0, 85 (m, 8H), 1.63 (m, 2H), 6.48 (m, 3H), 7.4 (broad) .s, 1H) PKMZ: APC1 ⁺ : t / ζ 277 [MH ⁺ ]; APC1: t / ζ 275 [M-H] ', (41% yield) 24 ^X H-NMR (400 MHz, COC1 ₃ ): δ = 0.75-0.86 (m, 8H), 1.64 (m, 2H), 6.65 (m, 1H), 7.02 (m , 1H); KMZ: APC1 ⁺ : t / ζ 295 [MH ⁺ ]; APC1 ': t / ζ 293 [M-H]', (41% yield)

Received 25-26.

Compounds of the general formula given above were prepared by a method similar to that described in Preparation 9, using chlorodiketone from Preparation 5 and a suitable phenol (Ag ₁ OH, commercially available or from Preparations 42) as starting materials.

Getting AG1- Analysis data T ^X H-NMR (400 MHz, COC1 ₃ ): 6 = 0.77-0.81 (m, 4H), 1.66 (m, 1H), 2.08 (s, 3H), 2.50 25 (s, 3H), 6.77 (d, 1H), 6.84 (s, 1H), 7.52 (d, 1H); LRMZ: APC1 ⁺ : t / ζ 254 [MH ⁺ ]; APC1 ': t / ζ 252 [M-H]'; (71% yield) ^X H-NMR (400 MHz, COC1 ₃ ): 6 = 0.76-0.82 (m, H ₃ C ^ and 4H), 1.67 (m, 1H), 2.08 (s, ZN), 2.47 26 (s, 6H); 6.64 (s, 2H); LKMZ: APC1 ⁺ : t / ζ sun ₃ 268 [MH ⁺ ]; APC1 ': t / ζ 266 [M-H]'; (62% yield) '

Getting 27.

Compounds of the general formula given above were obtained by a method similar to that described in Preparation 9, using commercial 3-chloro-2,4-pentanedione and a suitable phenol (Ag ₁ OH) as starting materials.

- 26 014693

Getting AG1 ~ Analysis data 27 ϊ CH, ^X H-NMR (400 MHz, CPC1 ₃ ): δ = 2.12 (s, 6H), 2.47 (s, 6H), 6.62 (s, 2H); LKMZ: ARP ⁺ : τη / ζ 242 [MH ⁺ ]; APC1 ”: t / ζ 240 [M-H]”; (55% yield)

Receive 28-29.

ΊΧ Oh

Compounds of the general formula given above were obtained by a method similar to that described in Preparation 9, using, as starting materials, chlordiketone from Preparation 6 and a suitable phenol (Cr1OH), _______________________________________________________________

Getting AG1 ~ Analysis data 28 YU ^X H-NMR (400 MHz, CbCl ₃ ): 6 = 1.14 (τ, 6H), 2.48 (q, 4H), 6.95 (d, 2H), 7.58 (d, 2H), 10.31 (br s, 1H); LKMZ: APC1 ⁺ : t / ζ 242 [MH ⁺ ]; APC1 ”: t / ζ 240 [M-H]; (45% yield) 29th BUT? sun ₃ ^X H-NMR (400 MHz, CbCl ₃ ): δ = 1.17 (τ, 6H), 2.47-2.50 (m, UN), 6.62 (s, 2H); LKMZ: APC1 ⁺ : t / ζ 270 [MH ⁺ ]; ARSG: t / ζ 268 [ΜΗ] ”; (49% yield)

Receipts 30-31.

Compounds of the general formula given above were prepared by a method similar to that described for Preparation 9, using 4-cyanophenol and the appropriate chlorodiketones described in Preparations 7 and 8 as starting materials.

Getting KZ, K 4 Analysis data thirty Bvi, gvi ^X H-NMR (400 MHz, CBS1 ₃ ): δ = 1.2 (s, 18H), 6.95 (d, 2H), 7.58 (d, 2H), 10.0 (br s, 1H ); LKMZ: APC1 ⁺ : t / ζ 298 [MH ⁺ ]; ARSG: t / ζ 296 [M-H] ”; (37% yield) 31 Me bb ^X H-NMR (400 MHz, COC1 ₃ ): δ = 1.25 (s, 9H), 2.0 (s, 3H), 6.95 (d, 2H), 7.58 (d, 2H), 8.0 (br s, 1H); LKMZ: ARSG: t / ζ 256 [MH ⁺ ]; ARSG: t / ζ 254 [M-H] '; (44% yield)

Preparation 32. 4- (3-Oxo-2-propionylpentyl) benzonitrile.

Sodium hydride (60% dispersion in oil, 3.43 g, 86 mmol) was added under nitrogen to a solution of 3,5-heptanedione (10 g, 78 mmol) in 2-butanone (200 ml). A slight exothermic effect was observed during gas evolution. Then sodium iodide (11.7 g, 78 mmol) was added, followed by 4-cyanobenzyl bromide (15.29 g, 78 mmol) in 2-butanone (20 ml), and a precipitate formed. The reaction mixture was refluxed for 16 hours. The mixture was then filtered to remove the precipitate and concentrated under reduced pressure. The residue was stirred in dichloromethane (100 ml) and solid sodium bromide was removed by filtration. The dichloromethane filtrate was washed with water (100 ml) and brine (100 ml). The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an orange solid.

It was suspended in diethyl ether and filtered off to give the title compound (11.01 g, 58%) in the form of a light yellow solid.

¹ H NMR (400 MHz, SPS13): δ = 0.98 (t, 6H), 2.29-2.35 (m, 2H), 2.42-2.52 (m, 2H), 3.19 (d, 2H), 3.97 (t,

- 27 014693

1H). 7.25 (d. 2H). 7.56 (d. 2H); BKM8: ARSG: t / ζ 242 [M-H].

Preparation 33. 4 - [(3.5-Diethyl-1H-pyrazol-4-yl) methyl] benzonitrile

The target compound (4.9 g. 45%) was obtained by the method. similar to that described in stage 2 of production 9. using diketone from preparation 32 and hydrazine as starting materials.

¹ H NMR (400 MHz. SES _{1 3} ): δ = 1.16 (t. 6H). 2.51 (q. 4H). 3.82 (s. 2H). 7.20 (d. 2H). 7.55 (d. 2H); BKM8: ARS! ⁺ : t / ζ 240 [MH ⁺ ].

Preparation 34. 4- (2-Cyclopropyl-2-oxoethoxy) -2.6-dimethylbenzonitrile.

Bromine (12.84 ml. 250 mmol) was added dropwise over 10 min in a nitrogen atmosphere to an ice-cooled solution of cyclopropylmethylketone (21 g. 250 mmol) in methanol (150 ml). Reactions were allowed to proceed at internal temperature. maintained below 10 ° C. before discoloration. The reaction mixture was stirred at room temperature for another 30 minutes. Water (75 ml) was added and the reaction mixture was stirred for another 15 minutes. The mixture was diluted with water (225 ml) and extracted 4 times with diethyl ether (4x250 ml). The organic layers were combined. washed with 10% aqueous sodium bicarbonate solution (250 ml). then water (250 ml). then saline (250 ml). then dried over magnesium sulfate. filtered and concentrated under reduced pressure. getting 2-bromo-1-cyclopropylethanone.

Cesium carbonate (30.7 g. 111.16 mmol) was added to a solution of 4-hydroxy-2.6-dimethylbenzonitrile (15.27 g. 101.89 mmol) in acetone (377 ml). Then, 2-bromo-1-cyclopropylethanone (15.1 g, 62.6 mmol) in acetone (100 ml) was added dropwise to the suspension over 5 minutes, and the reaction mixture was heated under reflux for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous potassium carbonate (300 ml) and dichloromethane (300 ml). The organic layer was separated and washed with brine (250 ml). dried over magnesium sulfate. filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a dichloromethane: pentane mixture (50:50 to 80:20; v / v). obtaining the target compound (13.5 g. 64%) in the form of a solid.

¹ H NMR (400 MHz. SES _{1 3} ): δ = 0.97-1.01 (m 2H). 1.12-1.15 (m. 2H). 2.19 (m. 1H). 2.47 (p. 6H). 4.71 (s. 2H). 6.61 (s. 2H); BKM8: ARSG: 230 [MH ⁺ ]

Preparation 35. 4- {[(Ε / Ζ) -1 - (Cyclopropylcarbonyl) -2- (dimethylamino) vinyl] oxy} -2.6-dimethylbenzonitrile.

Benzonitrile from Preparation 34 (11.8 g. 51.46 mmol) and Ν.Ν-dimethylformamide dimethylacetal (13.7 ml. 102.93 mmol) was heated at 105 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a dichloromethane: pentane mixture (50:50. Then 80:20. Then 100: 0. By volume). obtaining the target compound (11.19, 76%) in the form of a white solid.

¹ H NMR (400 MHz. SES _{1 3} ): δ = 0.63 (broad s, 2H). 0.91 (broad s. 2H). 1.93 (m, 1H). 2.44 (p. 6H). 2.96 (p. 6H). 6.69 (s. 2H); BKM8: ARSG: 285 [MH ⁺ ].

Preparation 36. 4 - [(3-Cyclopropyl-1H-pyrazol-4-yl) oxy] -2.6-dimethylbenzonitrile.

Benzonitrile from Preparation 35 (11.19 g. 39.3 mmol) was dissolved in acetic acid (62 ml). Hydrazine hydrate (2.11 ml. 43.6 mmol) was added and the mixture was stirred at room temperature for 12 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (150 ml) and diethyl ether (200 ml). Organic layer drying

- 28 014693 over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the target compound (9.71 g, 98%) in the form of a solid.

¹ H NMR (400 MHz, CBC1 ₃ ): δ = 0.82-0.88 (m, 4H), 1.73 (m, 1H), 2.47 (s, 6H), 6.70 (s, 2H), 7.41 (s, 1H), 10.5 (br s, 1H); LKM8: ARSG: t / ζ 254 [MH ⁺ ]; ARSG: t / ζ 252 [M-H] ^- .

Preparation 37. 4 - [(3-Cyclopropyl-1-tetrahydro-2H-pyran-2-yl-1H-pyrazol-4-yl) oxy] -2,6-dimethylbenzonitrile.

p-Toluenesulfonic acid (20 mg, 0.12 mmol) was added to a solution of benzonitrile from Preparation 36 (1 g, 3.94 mmol) in tetrahydrofuran (30 ml). 3,4-Dihydro-2H-pyran (664 mg, 7.9 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 15 hours. It was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate (100 ml). The organic layer was washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the target compound (1.33 g, 100%).

¹ H NMR (400 MHz, REDD: δ = 0.74-0.79 (m, 2H), 0.83-0.87 (m, 2H), 1.54-1.76 (m, 5H), 1.85 (m, 1H), 2.47 (s, 6H), 3.51 (m, 1H), 3.68 (m, 1H), 3.88 (m, 1H), 4.09 (m , 1H), 6.70 (s, 2H), 7.40 (s, 1H), mixed with a certain amount of 3,4-dihydro-2H-pyran; LKM8: ARSG: t / ζ 338 [MH ⁺ ] and t / ζ 254 [M-THP].

Get 38 and 39. 4 - [(5-Chloro-3-cyclopropyl-1-tetrahydro-2H-pyran-2-yl-1H-pyrazol-4-yl) oxy] -

U-Chlorosuccinimide (764 mg, 5.71 mmol) was added to a solution of pyrazole from Preparation 37 (1.33 g, 3.9 mmol) in U, U-dimethylformamide (30 ml). The reaction mixture was heated at 50 ° C. for 15 hours. Then it was evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate: pentane (gradient from 2:98 to 30:70, v / v) to give the compound from Preparation 38 (388 mg, 18%), eluting first.

¹ H NMR (400 MHz, REDD: δ = 0.65 (m, 1H), 0.84-0.92 (m, 3H), 1.60-1.63 (m, 2H), 1.68- 1.73 (m, 3H), 1.94 (m, 1H), 2.14 (m, 1H), 2.48 (s, 7H), 3.67 (t, 1H), 5.50 (d , 1H), 6.62 (s, 2H); LKM8: ARSG: t / ζ 288 [(M-THP) H ⁺ ].

Further elution gave the compound from Preparation 39 (325 mg, 20%).

¹ H NMR (400 MHz, CBC1 ₃ ): δ = 0.80-0.82 (m, 2H), 0.86-0.94 (m, 2H), 1.74 (m, 1H), 2, 49 (s, 6H); 6.65 (s, 2H); LKM8: ARSG: t / ζ 288 [MH ⁺ ]; ARSG: t / ζ 286 [M-H].

Preparation 40. 4- (3,5-Dicyclopropyl-1-hydroxymethyl-1H-pyrazol-4-yloxy) benzonitrile.

A mixture of pyrazole from Preparation 9 (2.9 g, 10.9 mmol) and an aqueous solution of formaldehyde (37 wt.% Solution in water, 40 ml) was heated at 60 ° C. for 4 hours. The mixture was cooled, partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml) and the layers were separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride (3x30 ml) and then with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude target compound in the form of a semi-solid (4.6 g,> 100% due to the presence of impurities).

¹ H NMR (400 MHz, CBC1 ₃ ): δ = 0.78-0.82 (m, 8H), 1.6 (m, 2H), 5.55 (s, 2H), 7.0 (d, 2H), 7.6 (d, 2H); LKM8: ARSG: t / ζ 296 [MH ⁺ ].

- 29 014693

Preparation 41. 4- (1-Chloromethyl-3.5-dicyclopropyl-1H-pyrazol-4-yloxy) benzonitrile.

Thionyl chloride (1.14 ml. 15.2 mmol) was added to a solution of crude hydroxymethylpyrazole from Preparation 40 (approximately 10.9 mmol of crude compound) in dichloromethane (50 ml). The mixture was stirred at room temperature for 24 hours. Then another part of thionyl chloride (1.14 ml. 15.2 mmol) was added and stirring was continued for an additional 90 minutes. The mixture was evaporated under reduced pressure and subjected to an azeotropic treatment with toluene (5x30 ml). obtaining the crude target compound in the form of a solid (3.8 g).

¹ H NMR (400 MHz. SEC): δ = 0.78-0.82 (m, 8H). 1.55 (m, 1H). 1.60 (m, 1H). 5.9 (p. 2H). 7.0 (d. 2H). 7.6 (d. 2H).

Getting 42. Benzonitrile 4-hydroxy-2-methyl.

Boron chloride (1 M in dichloromethane. 747 ml. 747 mmol) was added dropwise under a nitrogen atmosphere at -78 ° C over 40 minutes to a suspension of commercially available 4-methoxy-2-methylbenzonitrile (44 g. 298 mmol) and tetrabutylammonium iodide (121 g. 327 mmol) in dichloromethane (750 ml). Immediately upon completion of the addition, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was quenched by adding dropwise water. keeping the internal temperature below 10 ° C. The mixture was filtered through Arbose1 ™ and the layers were separated. The aqueous layers were re-extracted with dichloromethane (250 ml). The organic layers were combined. washed with sodium thiosulfate solution (150 ml). dried over magnesium sulfate. filtered and concentrated under reduced pressure. getting a thick yellow oil. Trituration of this oil in dichloromethane followed by filtration gave the first yield of the target compound (10.8 g, 27%) in the form of a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel. eluting with pentane: ethyl acetate (70:30. v / v). obtaining an additional yield of the target compound in the form of a white solid (14.4 g. 36%).

¹ H NMR (400 MHz. SEC): δ = 2.46 (s. 3H). 6.68 (d. 1H). 6.72 (s. 1H). 7.45 (d. 1H); LKM8: ARSG: t / ζ 132 [M-H] '.

Preparation 43. 5-Methoxyquinolin-8-yl ester of trifluoromethanesulfonic acid.

Trifluoromethanesulfonic anhydride (12 ml. 77.0 mmol) was slowly added. in about 5 minutes at 0 ° С in a nitrogen atmosphere to a stirred solution of 5-methoxy-quinolin-8-ol (8ui1N. Sotti .. 1997.27 (20). 3573-3579) (1.5 g. 8.6 mmol) and pyridine (5.5 ml. 68.5 mmol) in dichloromethane (34 ml). The resulting mixture was allowed to warm to room temperature and stirred for another 16 hours. The mixture was partitioned between dichloromethane (100 ml) and saturated aqueous ammonium chloride (100 ml). The organic extract was washed with water (100 ml). dried over magnesium sulfate. filtered and concentrated under reduced pressure. getting a crude yellow solid. Purification by flash chromatography on silica gel. eluting with 5% ethyl acetate. 95% pentane. the desired compound was obtained in the form of a pale yellow solid (2.62 g. 99%).

¹ H NMR (400 MHz. SEC): δ = 4.02 (s. 3H). 6.79 (d. 1H). 7.50 (m, 2H). 8.58 (dd. 1H). 9.03 (dd. 1H); LKM8: APC1 ⁺ : t / ζ 308 [MH ⁺ ].

Preparation 44. 5-Methoxyquinoline-8-carbonitrile.

Sodium cyanide (835 mg. 17.0 mmol). tetrakis (triphenylphosphine) palladium (492 mg. 0.42 mmol). copper (1) iodide (162 mg. 0.85 mmol) and the product from Preparation 43 (2.62 g. 8.52 mmol) were mixed in a 250 ml round-bottom flask and purged with nitrogen. Acetonitrile (43 ml) was added and the resulting mixture was refluxed under nitrogen for 2 hours. The mixture was diluted with ethyl acetate (200 ml) and filtered through Arbose1 ™. The filtrate was washed with water (100 ml). dried over magnesium sulfate. filtered and concentrated under reduced pressure. The crude product was purified flash chromium

- 30 014693 by silica gel printing, eluting with ethyl acetate: pentane (gradient from 10:90 to 30:70, v / v), to give the title compound as a pale yellow solid (1290 mg, 82%).

¹ H NMR (400 MHz, SES1 ₃ ): δ = 4.08 (d, 3n), 6.90 (d, 1H), 7.51 (dd, 1H), 8.06 (d, 1H), 8 62 (dd, 1H); 9.09 (dd, 1H); LKM8: ARSG: t / ζ 185 [MH ⁺ ].

Preparation 45. 5-Hydroxyquinoline-8-carbonitrile.

To a stirred solution of carbonitrile from Preparation 44 (750 mg, 4.1 mmol) in 1-methylpyrrolidinone (20 ml) at room temperature under nitrogen atmosphere was added in one part sodium thiophenolate (673 mg, 6.1 mmol). The resulting mixture was heated at 200 ° C for 14 hours. The mixture was partitioned between diethyl ether (100 ml) and 1N. aqueous solution of HaON (50 ml). The aqueous phase was acidified with 1N. HCl (~ 50 ml) was extracted with diethyl ether (2x50 ml) and the organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the target compound in the form of a yellow solid (210 mg, 30%).

¹ H NMR (400 MHz, 6-6 acetone): δ = 7.15 (d, 1H), 7.63 (m, 1H), 8.11 (dd, 1H), 8.70 (d, 1H) 9.07 (m, 1H); 9.09 (dd, 1H); LKM8: ARSG: t / ζ 171 [MH ⁺ ].

Example 1. 4- (3,5-Dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile.

Stage 1

Pyrazole from Preparation 9 (10 g, 37.7 mmol) was dissolved in dimethoxyethane (200 ml). Potassium tert-butoxide (4.65 g, 42 mmol) was added to this solution, and then the mixture was heated at 60 ° C for 30 minutes. Chloromethyl methyl sulfide (4 g, 42 mmol) was added and the reaction temperature was maintained at 60 ° C for 2 hours. TLC analysis showed an incomplete reaction, so the following parts of potassium tert-butoxide (2 g, 18 mmol) and chloromethyl methyl sulfide (2 g, 21 mmol) were added. . After an additional 90 minutes, the reaction mixture was cooled and partitioned between diethyl ether (500 ml) and 2N. aqueous sodium hydroxide solution (200 ml). The layers were separated and the aqueous layer was extracted with diethyl ether (100 ml). The organic extracts were combined and washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to give a crude intermediate (4- (3,5-dicyclopropyl-1-methylsulfanylmethyl-1H-pyrazol-4-yloxy) benzonitrile) in the form yellow oil (note: this intermediate can be purified by silica gel chromatography, eluting with ethyl acetate: pentane, or used in step 2 as a crude sulfide).

Stage 2

Okope® (30 g, 49 mmol) was added to a solution of the intermediate of step 1 in methanol (500 ml) and water (40 ml). The reaction mixture was stirred at 60 ° C for 18 hours and the next portion of Ohope® (10 g, 16 mmol) was added. After an additional 2 hours at 60 ° C, the mixture was partitioned between diethyl ether (800 ml) and 1N. aqueous sodium hydroxide solution (300 ml). The layers were separated and the aqueous layer was extracted twice with diethyl ether (2x100 ml). The organic extracts were combined and washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to give a yellow solid. This solid was purified by silica gel chromatography, eluting with ethyl acetate: pentane (1: 1), to give the target compound (7.4 g). This solid was recrystallized from ethanol to give the pure target compound (5.4 g, 40%). ¹ H NMR (400 MHz, SPS1 ₃ ): δ = 0.71 (m, 2H), 0.78-0.85 (m, 6H), 1.58 (m, 1H), 1.72 (m, 1H), 3.03 (s, 3H), 5.26 (s, 2H), 6.99 (d, 2H), 7.61 (d, 2H); LKM8: ARSH: t / ζ 358 [mH ⁺ ]; so pl. 141.5-142.5 ° C.

Examples 2-16.

Compounds of the general formula above were prepared using a method similar to that described in Example 1, using pyrazoles from Preparations 10-24.

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2H), 0.78-0.81 (m, 4H), 2H), 1,58 (m, 1H) 1.72 (from, ZN) 3.02 (from, ZN) 6.76 (d 1H) 6.86 (from,

2H), 0.78-0.83 (m, 4H), 2H), 1,56 (m, 1H) 1, 72 (from, ZN) 5.25 (from, 2H), 7.07 (from, 1H) 7.61 (d,:

Ή-NMR (400 MHz, СОС1з) : 5 = 0, 81 (m, 4H) 1, 60 (m, 1H) 1.71 (m, 1H) 3, 03 (from, 1H) 5.26 (s, 1H) 6.82 (d, , 1H) 7, 49 (dd, 1H) 7 74 (d, 1H); BKMZ : APC1 ha / ζ 392 [MH ⁺ ]; ¹ (75% yield)

- 32 014693

8 "ABOUT' ^ -NMR (400 MHz, СОС1 ₃ ): 6 = 0.72-0.85 (m, 8Н), 1.59 (m, 1Н), 1.73 (s, 1Н), 3.00 (s, ZN), 3.98 (s, ZN), 5.25 (s, 2H), 6.72 (d, 1H), 7.20 (m, 2H); LEMZ: APC1 ⁺ : t / ζ 38 8 [MH ⁺ ]; (70% yield) nine ^ -NMR (400 MHz, СОС1 ₃ ): 5 = 0.65-0.74 (m, 8Н), 1.51 (m, 1Н), 1.70 (m, 1Н), 2.99 (s, ZN), 5.22 (s, 2H), 6.63 (d, 1H), 7.64 (m, 1H), 7.71 (m, 2H), 8.18 (d, 1H), 8, 42 (d, 1H); LNMZ: APC1 ⁺ : t / ζ 408 [MH ⁺ ]; (90% yield) 10 ^ -NMR (400 MHz, СОС1з): 5 = 0.72-0.77 (m, 8Н), 1.50 (m, 1Н), 1.71 (s, 1Н), 3.00 (s, ЗН ), 5.23 (s, 2H), 6.71 (d, 1H), 7.56 (dd, 1H), 7.96 (d, 1H), 8.72 (dd, 1H), 9.11 (dd, 1H); LNMZ: APC1 ⁺ : t / ζ 409 [MH ⁺ 1; (85% yield) eleven V ^ -NMR (400 MHz, СОС1 ₃ ): 5 = 0.69-0.87 (m, 8Н), 1.58 (m, 1Н), 1.76 (m, 1Н), 3.03 (s, ZN), 5.27 (s, 2H), 6.61 (d, 1H), 7.63 (τ, 1H), 7.80 (m, 1H), 8.19 (d, 1H), 8, 37 (d, 1H); 8.72 (d, 1H); LNMZ: APC1 ⁺ : t / ζ 384 [MH ⁺ ]; (69% yield) 12 No. ^ -NMR (400 MHz, СОС1 ₃ ): 5 = 0.65-0.74 (m, 8Н) 1.59 (m, 1Н) 1.73 (m, 1Н) 3.02 (s, ЗН) 5 25 (s, 2H) 6.64 (m, 1H); 6.75 (m, 1H); 7.30 (m, 1H); LKMZ: APC1 ⁺ : t / ζ 385/387 [MH ⁺ ]; (80% yield) thirteen ^X H-NMR (400 MHz, COC1 ₃ ): 5 = 0.65-0.74 (m, 8H) 1.59 (m, 1H) 1.73 (m, 1H) 3.02 (s, 3H) 5.25 (s, 2H) 6.60 (m, 1H), 6.76 (m, 1H), 7.08 (m, 1H); GCM5: APC1 ⁺ : t / ζ 369 [MH ⁺ ]; (75% yield) 14 R ¹ H-NMR (400 MHz, COC1 ₃ ): 5 = 0.73 (m, 2H), 0.81 (m, 2H), 0.88 (m, 2H), 1.13 (d, 2H), 1.59 (m, 1H), 1.73 (m, 1H), 3.02 (s, 3H), 5.25 (s, 2H), 6.55 (dd, 2H); KMZ: APC1 ⁺ : t / ζ 387 [MH ⁺ ]; (50% yield) fifteen R ^ -NMR (400 MHz, СОС1 ₃ ): 5 = 0.65-0.74 (m, 8Н), 1.59 (m, 1Н), 1.73 (m, 1Н), 3.02 (s, ZN), 5.25 (s, 2H), 6.40-6.55 (m, ZN); KMZ: APC1 ⁺ : t / ζ 369 [MH ⁺ ]; (77% yield) sixteen ^ -NMR (400 MHz, СОС1 ₃ ): 5 = 0.65-0.74 (m, 8Н), 1.59 (m, 1Н), 1.73 (m, 1Н), 3.02 (s, ZN), 5.25 (s, 2H), 6.65 (m, 1H), 7.04 (m, 1H); LKMZ: APC1 ⁺ : t / ζ 387 [MH ⁺ ]; (78% yield)

Examples 17-20.

regioisomer 1 regioisomer 2

Compounds of the general formulas given above were obtained by a method similar to that described in example 1 using pyrazoles from preparations 25-26. The regioisomers were separated using silica gel chromatography, with regioisomer 1 eluting before regioisomer 2.

- 33 014693

Example Νο AG1 ~ Analysis data 17, 18 Regioisomer 1: ^X H-NMR (400 MHz, SES1 ₃ ): 5 = 0.78-0.82 (m, 4H), 1.60 (m, 1H), 2.18 (s, 3H), 2, 51 (s, 3H), 2.97 (s, 3H), 5.11 (s, 2H), 6.76 (d, 1H), 6.84 (s, 1H), 7.53 (d, 1H) ); PRIZE: APC1 ⁺ : t / ζ 346 [MH ⁺ ]; (35% yield) Regioisomer 2: ¹ H-NMR (400 MHz, COC1 ₃ ): 5 = 0.70-0.73 (m, 2H), 0.85-0.89 (m, 2H), 1, 73 (m, 1H), 2.03 (s, 3H), 2.51 (s, 3H), 3.06 (s, 3H), 5.30 (s, 2H), 6.72 (d, 1H ), 6.81 (s, 1H), 7.53 (d, 1H); LIMZ: APC1 ⁺ : t / ζ 346 [MH ⁺ ]; (25% yield) 19, 20 CH Regioisomer 1: ¹ Η-ΝΜΚ (400 MHz, СРС1 ₃ ): 5 = 0.80-0.83 (m, 4Н), 1.63 (m, 1Н), 2.17 (s, ЗН), 2, 48 (s, 6H), 2.97 (s, 3H), 5.12 (s, 2H), 6.63 (s, 2H); BKMZ: APC1 ⁺ : t / ζ 360 [MH ⁺ ], (30% yield) 2: ¹ H-NMR regioisomer (400 MHz, СОС1 ₃ ): 5 = 0.71-0.73 (m, 2Н), 0 85-0.88 (m, 2H), 1.75 (m, 1H), 2.01 (s, 3H), 2.47 (s, 6H), 3.05 (s, 3H), 5, 29 (s, 2H); 6.59 (s, 2H); ΙΉΜ3: APC1 ⁺ : t / ζ 360 [MH ⁺ ], (22% yield)

Example 21

Compounds of the general formula above were prepared by a method similar to that described in Example 1 using pyrazole from Preparation 27.

Example No. AP Analysis data 21 sun ₃ ^X H-NMR (400 MHz, COC1 ₃ ): 5 = 2.06 (s, 3H), 2.20 (s, 3H), 2.48 (s, 6H), 3.00 (s, 3H), 5.15 (s, 2H); 6.60 (s, 2H); 1-8: APC1 ⁺ : t / ζ 334 [MH ⁺ ]. (86% yield)

Examples 22-23.

Compounds of the general formula given above were prepared by a method similar to that described in Example 1 using pyrazoles from Preparations 28-29.

Example No. Αγι- Analysis data 22 Ή ^X H-NMR (400 MHz, CPC1 ₃ ): 5 = 1.12 (t, 6H), 2.40 (q, 2H), 2.64 (q, 2H), 3.02 (s, 3H), 5.17 (s, 2H), 6.96 (d, 2H), 7.60 (d, 2H); LKMZ: APC1 ⁺ : t / g 334 [MH ⁺ ], (88% yield) 23 SNZ ^X H-NMR (400 MHz, COC1 ₃ ): 5 = 1.13 (t, 6H), 2.41 (q, 2H), 2.47 (s, 6H), 2.64 (q, 2H), 3.01 (s, 3H); 5.17 (s, 2H); 6.61 (s, 2H); 1ΉΜΞ: APC1 ⁺ : t / ζ 362 [MH ⁺ ]; (90% yield)

- 34 014693

Examples 24-26.

Compounds of the general formula. above. were obtained by the method. similar to that described in example 1. using pyrazoles from obtaining 30-31. The regioisomers 25 and 26 were separated by chromatography. where 25 elutes before 26.

Example No. KZ, K 4 Analysis data 24 EVI, EVI ^: H NMR (400 MHz, SOS1 _3): 5 = 1.15 (s, 9H), 1.3 (s, 9H), 3.2 (s, SH), 5.4 (s, 2H) 6.96 (d, 2H); 7.60 (s, 2H); BNMZ: ARSG: t / ζ 390 [MH ⁺ ], (50% yield) 25 Me, EVi ^X H-NMR (400 MHz, COC1 ₃ ): 5 = 1.2 (s, 9H), 2.1 (s, 3H), 3.0 (s, 3H), 5.15 (s, 2H), 6.96 (d, 2H); 7.60 (d, 2H); KMZ: ARSG: t / ζ 34 8 [MH ⁺ ], (10% yield) 26 EVI, Me ^ -NMR (400 MHz, COC1 ₃ ): 5 = 1.4 (s, 9H), 1.95 (s, 3H), 3.15 (s, 3H), 5.4 (s, 2H), 6 96 (d, 2H); 7.60 (d, 2H); LKMZ: APC1 ⁺ : t / ζ 348 [MH ⁺ ], (5% yield)

Examples 27 and 28. 4- (3-Chloro-5-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6 dimethylbenzonitrile and 4- (5-chloro-3-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazole -4-yloxy) -2.6 dimethylbenzonitrile.

Examples 27 and 28 were obtained by the method. similar to that described in example 1. using pyrazole from obtaining 39. but the regioisomers were isolated in the form of a mixture of 40:60.

¹ H NMR (400 MHz. SES1 ₃ ): δ = 0.78-0.80 (m. 2H. Major regioisomer A). 0.84-0.88 (m. 4H. Minor regioisomer B). 0.93-0.96 (m 2H. A). 1.69 (m, 1H. A). 1.79 (m, 1H. B). 2.50 (p. 6H. A + B). 3.04 (p. 3H. B). 3.10 (p. 3H. A). 5.19 (p. 2H. B). 5.31 (p. 2H. A). 6.62 (p. 2H. A). 6.67 (p. 2H. B); LKM8: ARSG t / ζ 380 [MH ⁺ ].

regioisomer 1

regioisomer 2

Compounds of the general formula. above. were obtained by the method. similar to that described in example 1. using pyrazole from obtaining 36. The regioisomers were separated. using chromatography on silica gel. moreover, regioisomer 1 elutes before regioisomer 2 .______________

Example No. Analysis data 29th Regioisomer 1: ^X H-NMR (400 MHz, COC1 ₃ ): δ = 0.85 (m, 4H) 1.66 (m, 1H) 2.48 (s, 6H) 2.90 (s, 3H) 5 13 (s, 2H) 6.70 (s, 2H) 7.48 (s, 1H); LKMZ: APC1 ⁺ : t / ζ 346 [MH ⁺ ]; (32% yield) thirty Regioisomer 2: ^ -NMR (400 MHz, COC1 ₃ ): 5 = 0.75 (m, 2H) 0.91 (m, 2H) 1.77 (m, 1H) 2.48 (m, 6H) 3, 05 (s, 3H); 5.36 (s, 2H); 6.65 (s, 2H); 7.39 (s, 1H); LKMZ: ARSG: t / ζ 346 [MH +]; (4% yield)

Example 31. 4 - ({3.5-Diethyl-1 - [(methylsulfonyl) methyl] -1 H-pyrazol-4-yl} methyl) benzonitrile.

- 35 014693

The target compound (123 mg, 87%) was obtained by a method similar to the method of example 1, using pyrazole from obtaining 33.

¹ H NMR (400 MHz, COC1 ₃ ): δ = 1.04-1.12 (m, 6H), 2.40 (q, 2H), 2.67 (q, 2H), 3.00 (s, 3H), 3.82 (s, 2H), 5.20 (s, 2H), 7.19 (d, 2H), 7.56 (d, 2H); LKM8: ARSG: t / ζ 332 [MH ⁺ ].

Example 32. 4- (3,5-Dicyclopropyl-1-trifluoromethanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile.

Stage 1

Cu8CP ₃ (0.21 g, 1.28 mmol) was added to a solution of chloromethylpyrazole from 41 (0.2 g, 0.64 mmol) in dimethylformamide (10 ml) and stirred for 3 days at room temperature. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x20 ml). The combined organic extracts were washed with water (3x30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: pentane (10:90) to give an intermediate sulfide (75 mg, 31%). ¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.78-0.82 (m, 8H), 1.25 (m, 2H), 5.55 (s, 2H), 7.0 (d, 2H), 7.6 (d, 2H). LKM8: ARSG: t / ζ 380 [MH ⁺ ].

Stage 2

Ochois® (610 mg, 1 mmol) was added to a solution of the intermediate sulfide (75 mg) from step 1 in methanol (10 ml) and water (2 ml). The reaction mixture was stirred at room temperature for 18 hours and the next portion of Ochois® (244 mg, 0.2 mmol) was added. After an additional 24 hours, the mixture was partitioned between diethyl ether (30 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted twice with diethyl ether (2x10 ml). The organic extracts were combined and washed with brine (10 ml), dried over magnesium sulfate, filtered and evaporated to give a brown residue. The residue was purified by silica gel chromatography eluting with a gradient of 5-10% dichloromethane in pentane to give the target compound (16 mg, 20%).

¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.65-0.90 (m, 8H), 1.55 (m, 1H), 1.65 (m, 1H), 5.4 (s, 2H), 6.99 (d, 2H), 7.6 (d, 2H); LKM8: ARSG: t / ζ 412 [MH ⁺ ].

Example 33. 4- (3,5-Dicyclopropyl-1-ethanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile.

Stage 1

Sodium ethylthiolate (54 mg, 0.64 mmol) was added to a solution of chloromethylpyrazole from Preparation 41 (0.2 g, 0.64 mmol) in 1,4-dioxane (5 ml) and stirred for 18 hours at room temperature. The mixture was diluted with water (30 ml) and extracted with diethyl ether (2x20 ml). The combined organic extracts were washed with water (3x30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: pentane (10:90) to give the intermediate sulfide as a solid (135 mg, 70%).

¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.65-0.82 (m, 8H), 1.2 (t, 3H), 1.5 (m, 1H), 1.6 (m, 1H), 2.65 (q, 2H), 5.15 (s, 2H), 7.0 (d, 2H), 7.6 (d, 2H). LKM8: ARSG: t / ζ 340 [MH ⁺ ].

Stage 2

Ochois® (732 mg, 12 mmol) was added to a solution of the intermediate sulfide (135 mg) from step 1 in methanol (10 ml) and water (2 ml). The reaction mixture was stirred at room temperature for 18 hours and partitioned between diethyl ether (30 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted twice with diethyl ether (2x10 ml). The organic extracts were combined and washed with brine (10 ml), dried over magnesium sulfate, filtered and up

- 36 014693 trivial, receiving a solid residue. The residue was purified by silica gel chromatography eluting with a gradient of 5-10% dichloromethane in pentane to give the title compound as a colorless solid (59 mg, 40%).

¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.7-0.9 (m, 8H), 1.4 (t, 3H), 1.55 (m, 1H), 1.7 (m, 1H), 3.1 (q, 2H), 5.20 (s, 2H), 7.0 (d, 2H), 7.6 (d, 2H). LKM8: ARSG t / ζ 372 [MH ⁺ ].

Examples 34 and 35.

Compounds of the general formula given above were prepared by a method similar to that described in Example 33 using a suitable sodium alkylthiolate followed by oxidation using 0khoe®.

Example No. Kh- Analysis data 34 -CH (CH ₃ ) ₂ F-NMR (400 MHz, СОС1 ₃ ): δ = 0.7-0.9 (m, 8Н), 1.4 (d, 6Н), 1.55 (m, 1Н), 1.8 (m, 1H), 3.35 (m, 2H), 5.30 (s, 2H), 7.0 (d, 2H), 7.6 (d, 2H); LKMZ: ARSG: t / ζ 386 [MH ⁺ ], (31% yield in total) 35 -C (CH ₃ ) s F-NMR (400 MHz, СОС1 ₃ ): δ = 0.70 (m, 2Н), 0.79 (m, 4Н), 0.87 (m, 2Н), 1.45 (s, 9Н), 1 56 (m, 1H), 1.90 (m, 1H), 5.39 (s, 2H) 6.96 (d, 2H), 7.6 (d, 1H); KMZ (electrospray): t / ζ 422 [ΜΝβ ⁺ ], (29% yield in total)

Example 36. 4- (1-Benzenesulfonylmethyl-3,5-dicyclopropyl-1H-pyrazol-4-yloxy) benzonitrile.

The target compound (275 mg, 66% yield) was obtained by a method similar to that of Example 1, using pyrazole from Preparation 9 (265 mg, 1 mmol) and chloromethylphenyl sulfide instead of chloromethyl methyl sulfide in step 1, followed by oxidation using 0X0UE®, similar to the method used in stage 2.

¹ H NMR (400 MHz, SES1 ₃ ): δ = 0.45 (m, 2H), 0.60-0.70 (m, 4H), 0.88 (m, 2H), 1.40 (m, 1H), 1.77 (m, 1H), 5.40 (s, 2H), 6.98 (d, 2H), 7.55 (m, 2H), 7.6 (d, 2H), 7, 72 (m, 1H); 7.78 (m, 2H); KM8 (electrospray): t / ζ 420 [MH ⁺ ] (66% yield).

By controlling the 0hoe® equivalents during the oxidation of sulfide to sulfone, intermediate sulfoxide can be isolated. This is illustrated by the following examples 37 and 38.

Example 37. 4 - ({3,5-Diethyl-1 - [(methylsulfinyl) methyl] -1H-pyrazol-4-yl} oxy) -2,6-dimethylbenzonitrile.

0khoe® (0.5 equiv; 120 mg, 0.2 mmol) was added to a solution of part of the sulfide obtained in stage 1 of example 23 (130 mg, 0.39 mmol) in methanol (10 ml) and water (2 ml) . The reaction mixture was stirred at room temperature for 3 hours, after which it was evaporated in vacuo and the residue was partitioned between water (10 ml) and dichloromethane (15 ml). The organic layers were dried over magnesium sulfate, filtered and then evaporated. The resulting crude product was purified by flash chromatography on silica gel eluting with ethyl acetate: pentane (1: 1, v / v) to give the title compound (100 mg, 73%).

- 37 014693 ¹ H NMR (400 MHz, SES1 ₃ ): δ = 1.09-1.14 (m, 6H), 2.40 (q, 2H), 2.46 (s, 6H), 2.62 -2.66 (m, 5H), 5.02 (d, 1H), 5.16 (d, 1H), 6.61 (s, 2H); LKM8: APC1 ⁺ : t / ζ 346 [MH ⁺ ].

Example 38. 4 - ({3,5-Dimethyl-1 - [(methylsulfinyl) methyl] -1H-pyrazol-4-yl} hydroxy) -2,6-dimethylbenzo nitrile.

The target compound (145 mg, 63%) was obtained by a method similar to the method of example 37, using as starting materials part of the sulfide obtained in stage 1 of example 21, and Ohope® (0.5 equiv.).

¹ H NMR (400 MHz, SES1 ₃ ): δ = 2.06 (s, 3H), 2.21 (s, 3H), 2.47 (s, 6H), 2.64 (s, 3H), 4 98 (d, 1H); 5.16 (d, 1H); 6.60 (s, 2H); BKM8: APC1 ⁺ : t / ζ 318 [MH ⁺ ].

Example 39

Examples of certain compounds tested in Scheme 1.0 as described above with respect to the functional antagonism of progesterone are shown in the table below.

Claims (22)

CLAIM 1. The compound of formula (I) or a pharmaceutically acceptable derivative thereof, in which K ¹ and K ^{3 are} independently H, C _1-6 alkyl, Cz- ₈ cycloalkyl or halogen; K ² is C _1-6 alkyl, CE ₃ or aryl; a is 1 or 2; 4 5 7 8 4 5 K, K, K and K independently represent H, C _1-6 alkyl, C ^ alkyloxy, SU or halogen, or K and K or K ⁷ and K ⁸ , together with the ring to which they are attached, form an aryl or heterocyclic fused ring system; X is C or Ν; Υ is CH ₂ or O and K ⁶ is H, SU, or halogen, but when X is Ν, then K ^{6 is} absent. 2. The compound according to claim 1, in which K ¹ denotes C _1-6 alkyl or C _3-8 cycloalkyl. 3. The compound according to claim 1 or 2, in which K ² denotes C _1-6 alkyl. 4. The compound according to any one of claims 1 to ³ , in which K ³ denotes C _1-6 alkyl or C _3-8 cycloalkyl. 5. The compound according to any one of claims 1 to ⁴ , in which K ⁴ denotes N. 6. The compound according to any one of claims 1 to 5, in which K ⁵ denotes H, C _1-6 alkyl or halogen. 7. The compound according to any one of claims 1 to ⁴ , in which K ⁴ and K ⁵ together represent a phenyl or pyridinyl ring fused to the ring to which they are attached. 8. The compound according to any one of claims 1 to 7, in which K ⁶ denotes SU. 9. The compound according to any one of claims 1 to 8, in which K ⁷ denotes H, C _1-6 alkyl or halogen. 10. The compound according to any one of claims 1 to ⁹ , in which K ⁸ denotes N. 11. The compound according to any one of claims 1 to 10, in which Υ is O. 12. The compound according to claim 1, selected from 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3,5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile; - 38 014693 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 2-chloro-4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) benzonitrile; 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2-fluorobenzonitrile; 3-chloro-4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) benzonitrile; 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -3-fluorobenzonitrile; 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -3-methoxybenzonitrile; 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) naphthalene-1-carbonitrile; 5- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) -quinoline-8-carbonitrile; 4- (3.5-dicyclopropyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) quinoline; 4- (4-chloro-3-fluorophenoxy) -3.5-dicyclopropyl-1-methanesulfonylmethyl-1H-pyrazole; 3.5-dicyclopropyl-4- (3.4-difluorophenoxy) -1-methanesulfonylmethyl-1H-pyrazole; 3.5-dicyclopropyl-1-methanesulfonylmethyl-4- (3.4.5-trifluorophenoxy) -1H-pyrazole; 3.5-dicyclopropyl-4- (3.5-difluorophenoxy) - 1-methanesulfonylmethyl-1 H-pyrazole; 3.5-dicyclopropyl-1-methanesulfonylmethyl-4- (2.4.5-trifluorophenoxy) -1H-pyrazole; 4- (3-cyclopropyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile; 4- (5-cyclopropyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) -2-methylbenzonitrile; 4- (3-cyclopropyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) -2.6 dimethylbenzonitrile; 4- (5-cyclopropyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) -2.6 dimethylbenzonitrile; 4- (1-methanesulfonylmethyl-3.5-dimethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 4- (3.5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3.5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 4- (3.5-di-tert-butyl-1-methanesulfonylmethyl-1 H-pyrazol-4-yloxy) benzonitrile; 4- (3-tert-butyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (5-tert-butyl-1-methanesulfonylmethyl-3-methyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3-chloro-5-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6 dimethylbenzonitrile; 4- (5-chloro-3-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6 dimethylbenzonitrile; 4- (3-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 4- (5-cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 4- (3.5-diethyl-1-methanesulfonylmethyl-1H-pyrazol-4-ylmethyl) benzonitrile; 4- (3.5-dicyclopropyl-1-trifluoromethanesulfonylmethyl-1 H-pyrazol-4-yloxy) benzonitrile; 4- (3.5-dicyclopropyl-1-ethanesulfonylmethyl-1H-pyrazole-4yloxy) benzonitrile; 4- [3.5-dicyclopropyl-1- (propan-2-sulfonylmethyl) -1H-pyrazol-4-yloxy] benzonitrile; 4- [3.5-dicyclopropyl-1- (2-methylpropan-2-sulfonylmethyl) -1H-pyrazol-4-yloxy] benzonitrile; 4- (1-benzenesulfonylmethyl-3.5-dicyclopropyl-1H-pyrazol-4-yloxy) benzonitrile; 4- (3.5-diethyl-1-methanesulfinylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile; 4- (3.5-diethyl-1-methanesulfinylmethyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile and their pharmaceutically acceptable derivatives. 13. 4- (3-Cyclopropyl-1-methanesulfonylmethyl-5-methyl-1H-pyrazol-4-yloxy) -2.6-dimethylbenzonitrile or a pharmaceutically acceptable derivative thereof. 14. The method of obtaining the compound according to claim 1. in which a denotes 1. including the oxidation of the compounds of formula (II) (P) - 39 014693 in which K? -K ⁸ , X and Υ have the meanings defined in paragraph 1. 15. The method of obtaining the compound according to claim 1, in which a is 2, comprising the oxidation of the compounds of formula (II) in which K? -K ⁸ , X and Υ have the meanings defined in claim 1. 16. The method for producing the compound according to claim 1, in which a is 2, comprising oxidizing a compound of formula (1a) (1a) in which K? -K ⁸ , X and Υ have the meanings defined above. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipient, diluent or carrier. 18. The use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable derivative or composition thereof as a medicine. 19. The use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable derivative or composition thereof, for the manufacture of a medicament for the treatment of endometriosis, uterine fibroids (leiomyomatous formations), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, difficulty in defecation and chronic pelvic pain) or chronic pelvic pain syndrome. 20. The use according to claim 19, where the disease or disorder is endometriosis and / or uterine fibroma (leiomyomatous lesions). 21. A method for treating endometriosis, uterine fibroids (leiomyomatous formations), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, difficult bowel movements and chronic pelvic pain) or chronic pelvic pain syndrome, comprising administering to the mammal an effective amount of a compound according to any one of claims. 1-13 or a pharmaceutically acceptable derivative or composition thereof. 22. The method according to item 21, where the disease or disorder is endometriosis and / or uterine fibroids (leiomyomatous lesions). Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2